CZ303462B6 - Imidazo[4,5-c]quinoline or 6,7,8,9-tetrahydroimidazo[4,5-c]quinoline derivative and pharmaceutical composition containing thereof - Google Patents

Abstract

In the present invention, there are disclosed imidazo- or tetrahydroimidazo[4,5-c]quinoline compounds of the general formula I or II, respectively in which the general symbols have specific meanings or pharmaceutically acceptable salts thereof. Disclosed is also a pharmaceutical composition containing thereof. The derivatives of the present invention are suited for the preparation of medicaments that are useful for inducing biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

Description

The area of those .ky io

This howl; ez relates to imidazo [4,5-u] quinoline or 6,7,8,9-tetrahydroimidazo [4,5-c] quinoline compounds having an ether and amide functional group at position 1, and pharmaceutical compositions (preparations). or compositions thereof). Another aspect of the invention is the large use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals, and for the treatment of diseases, including viral and tumor diseases.

BACKGROUND OF THE INVENTION

The first economical report on the 1H-imidazo [4,5-c] quinoline ring system, Backman and Kok, J, Org. Cl. 15, 1278-1284 (1950), describes the synthesis of 1- (6-methoxy-8-quinolinyl) -2-methyl-1H-imide 4,5-c] quinoline for possible use as an anti-malaria agent. Subsequently, a synthesis was announced; variously substituted 1H-imidazo [4,5-c-] quinolines. E.g. Jain et al., J. Med. Chem. 11, pp. 8 (1968), synthesized 1- [2- (4-piperidyl) ethyl] -1 H -imidazo [4,5- c] quinoline as a anticonvulsant and a cardiovascular agent. Also Baranov et al., Chem. Abs. 85, <62 (1976) reported several 2-oxoimidazo [4,5-c] quinolines, and Berenyi et al., J. Heterocyclic t. 18, 1537-1540 (1981), reported certain 2-oxoimidazo [4, 5-c] quinolines. Some 1H-imida, 4,5-cquinolin-4-amines and their 1- and 2-substituted derivatives were later found to be antiviral agents, bromide dilatants and immunomodulators. These compounds are described, inter alia, in U.S. Patent Nos. 4,689,338, 4,698,348, 4,929,624, 5,037,986, 5,268,376, 5,346,905, 389,640; all of which are incorporated herein by reference.

Interest in the azoquinoline ring system continues.

There are known some 1H-imidazo [4,5-c] naphthyridin-4-amines, 1H-imidazo [4,5-c] pyridin-4-amine, 1H-imido [4,5-c] quinolin-4-amines. having an ether-containing substituent at position 1. These compounds are disclosed in U.S. Pat. Nos. 5,268,376, 5,389,640, 5,494,916 and WO 99/29693.

In addition to attempts to find compounds that would be effective in inducing cytokine biosynthesis in humans, there remains a need for compounds that have the ability to modulate the immune response by inducing cytokine biosynthesis or other mechanisms.

The essence of the album

We have discovered a new class of compounds that are useful for inducing cytokine biosynthesis in animals. In this capacity, the compounds of the invention are effective as immune response modifiers ^; that they can be used to treat diseases which are susceptible to such changes in the immune response45; o are viral and tumor diseases,

Preform of formula I n &lt;

of the invention in the basic embodiment i) is the imidazo [4,5-c] quinoline derivative of the general formula) 6,7,8,9-tetrahydroimidazo [4,5-c] quinoline derivative of the general formula II

(AND)

X is -CHR ₅ - -CHR-alkyl or -CHRs-alkenyl-;

R 1 is selected from the group consisting of a residue

_{R 4} -CR 1 -ZR ₆ -alkyl;

-R ₄ -CR ₃ -ZR ₆ -alkenyl;

R i-C R i -Z-R f -aryl;

R 1 -C 1 R 2 -Z-R 5 -heteroaryl;

-R ₄ -CR ₃ -ZR ₆ -heterocyclyl;

R ₄ -CRx-ZH:

-R ₄ -NR ₇ -CR ₃ -R ₆ -alkyl;

_{R} NR7-CR3-R6-a]} alkenyl;

—R1 —NR2 —CR, —R4 —aryl;

-R ₄ -NR ₇ -R ₈ -R ₈ -heteroaryl; -R 1 -R y-CR 1 -R 1 -heterocycles]; and -R 4 -NR 7 -CR 3 -R ₈ ;

each Z independently represents -NR ₅ - -O- or -S-;

R ₂ is selected from the group consisting of residues

- a hydrogen atom;

- alkyl;

- 7.

alkenyl;

-aryl;

- heteroaryl;

- heterocyclyl;

alkyl-Y-alkyl;

- alkyl-Y-alkenyl;

alkyl-Y-aryl; and

alkyl or alkenyl substituted with one or more substituents selected from the group consisting of residues

-OH;

- halogen;

-N (R ₅ ) ₂ ;

-CO-N _{(R) 2;}

-CO-C 1-10 alkyl;

- CO - O - C 1-10 alkyl;

-N ₃ ;

-aryl;

- heteroaryl;

- heterocyclyl;

- CO-aryl; and

- CO-heteroaryl;

each R ₃ is = O or = S;

each R 4 independently represents alkyl or alkenyl, which may be interrupted by one or more -O- groups;

each R ₅ independently represents H or C 1-10 alkyl;

³⁰

R ₆ represents a bond, alkyl or alkenyl, which may be interrupted by one or more groups

-O-;

R ₇ represents H, C, _{_) O} 1 alkyl or aralkyl; or R 4 and R ₇ together form a saturated heterocyclic ring;

R ₈ is H or C _1-10 alkyl; or R ₇ and R ₈ together form a heterocyclic ring;

each Y independently represents -O- or -S (O) o -R 5 is 0 and 4; and each R present is independently selected from the group consisting of C _1-10 alkyl, C _1-10 alkoxy, hydroxy, halogen, and trifluoromethyl;

or a pharmaceutically acceptable salt thereof;

Wherein the alkyl group contains 1 to 10 carbon atoms;

an alkenyl group containing 2 to 10 carbon atoms;

aryl is selected from the group consisting of phenyl, naphthyl, biphenyl, fluorenyl and indenyl; heteroaryl is selected from the group consisting of fuyl, thienyl, pyridyl, quinolinyl, isoquinolines indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothienyl, carbazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl;

heterocycles is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl; and the aryl, heteroaryl and heterocyclyl groups may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, cyano, methoxy, trifluoromethyl and trifluoromethoxy.

Preferred embodiments of this aspect of the invention include, in particular, the following embodiments:

ii) an imidazo [4,5-c] quinoline derivative of the Formula I according to embodiment i), wherein X is -CH 1 -CH 2 -, or a salt thereof;

iii) an imidazo [4,5-c] quinoline derivative of Formula I or a 6,7,8,9-tetrahydroimidazo [4,5-c] quinoline derivative of Formula II according to embodiment i), wherein R ₂ is H, alkyl or -alkyl -O-alkyl, or salts thereof;

i) an imidazo [4,5-c] quinoline derivative of the Formula I or a 6,7,8,9-tetrahydroimidazo [4,5-c] quinoline derivative of the Formula II according to embodiment i), wherein R 1 is -R 4 -NRr -CR ₃ -R ₆ -alkyl or -R ₄ NR ₇ -CR ₃ -R ₆ -aryl, R ₃ represents = O, R ₇ represents a bond, and R ₇ represents H, or salts thereof;

v) an imidazo [4,5-c] quinoline derivative of Formula 1 or a 6,7,8,9-tetrahydroimidazo [4,5-c] quinoline derivative of Formula II according to embodiment i), wherein n is 0, or salts thereof;

The invention further provides (Embodiment of the Invention vi)) a pharmaceutical composition comprising a therapeutically effective amount of an imidazo [4,5-c] quinoline derivative of Formula I or a 6,7,8,9-tetrahydroimidazo [4,5-c] quinoline derivative of Formula II according to any one of embodiments i) to v), or a salt thereof, and a pharmaceutically acceptable carrier.

The invention further provides (embodiment of the invention vii)) the use of an imidazo [4,5-c] quinoline derivative of formula I or a 6,7,8,9-tetrahydroimidazo [4,5-cquinoline derivative of formula II according to any one of embodiments i) to v) or a salt thereof for the preparation of a medicament for inducing cytokine biosynthesis in the treatment of atopic diseases such as atopic dermatitis, asthma, allergy, allergic rhinitis;

in the treatment of systemic lupus erythematosus;

when used as an adjuvant for a vaccine for cell-mediated immunity;

in the treatment of chlamydia;

In the treatment of viral diseases including genital warts; common warts, foot warts, hepatitis B, hepatitis C, diseases caused by herpes simplex virus type I and type II, moluscum contagiosum, varriola major, HIV, CMV, VZV, rhinovirus, adenovirus, influenza and parainfluenza;

in the treatment of intraepithelial neoplasia, human papillomavirus (HPV) -induced diseases and associated neoplasia;

in the treatment of fungal diseases such as candidiasis, aspergillus infections and cryptococcal menini gitis;

in the treatment of cancers such as basocellular carcinoma, hairy cell leukemia, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgins lymphoma, T-cell skin lymphoma and other cancers;

in the treatment of parasitic diseases such as pneumocystis camii, ctyptosporidiosis, histoplasmosis, toxoplasmosis, trypanosomal infections and teishmaniasis;

in the treatment of bacterial infections such as tuberculosis and mycobacterium avium infections;

in the treatment of actinic keratosis, eczema, eosinophilia, essential thrombocythemia, leprosy, multiple sclerosis, Ommen's syndrome, discoid lupus, Bowen's disease, bowenoid papulosis, alopecia areata;

in the treatment of inhibiting colloidal formations of no surgery and other postoperative scars; in improving or stimulating wound healing, including chronic wounds; and in describing opportunistic infections and tumors that occur following suppression of cell-mediated immunity in transplant patients, cancer patients or HIV patients.

The invention furthermore relates to an embodiment of the invention (viii)) an imidazo [4,5-c] quinoline derivative of the general formula V

NH

where

X is -CHR ₅ -, -CHRs-alkyl-, or -CHR ₅ -aIkenyl-;

R? is selected from the group consisting of residues

- a hydrogen atom;

- alkyl;

alkenyl; -aryl;

- heteroaryl;

- heterocyclyl;

- alkyl-Y-alkyl;

- alkyl-Y-alkenyl;

alkyl-Y-aryl; and

alkyl or alkenyl substituted with one or more substituents selected from the group consisting of residues

-OH;

- halogen;

-N (R ₅ ) ₂ ;

-CO-N (R ₅ ) ₂ ;

-CO-C || _O alkyl;

-CO-O-C ₁₁₀ alkyl;

-N ₃ ;

-aryl;

- heteroaryl;

- heterocyclyl;

- CO-aryl; and

- CO-heteroaryl;

each R 4 independently represents alkyl or alkenyl, which may be interrupted by one or more -O- groups;

each R 5 independently represents H or C 1-10 alkyl;

R ₇ represents H, C | _O _i alkyl or arylalkyl 1; or R 4 and R ₇ together form a saturated heterocyclic ring;

each Y is independently -O- or -S (0) O_ ₂ -;

n is 0 to 4; and each R is independently selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, hydroxy, halogen, and trifluoromethyl, or a pharmaceutically acceptable salt thereof; wherein the alkyl group contains 1 to 10 carbon atoms;

an alkenyl group containing 2 to 10 carbon atoms;

aryl is selected from the group consisting of phenyl, naphthyl, biphenyl, fluorenyl and indenyl; heteroaryl is selected from the group consisting of furyl, thienyl. pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothienyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolinyl, benzothiazolinyl, benzothiazolinyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl;

The heterocycles are selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl; and the aryl, heteroaryl and heterocyclyl groups may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, cyano, methoxy, trifluoromethyl and trifluoromethoxy.

The derivative of the general formula V serves as an intermediate. In a preferred embodiment (embodiment exempted from ix), the derivative has a structure corresponding to the formula

In the following description, the invention is elucidated in a somewhat broader context than is within the scope of the present invention. It is therefore expressly stated that only the aspects explicitly mentioned above fall within the scope of the invention, and only those are also the subject of the appended claims. The following description is illustrative only.

Preparation of Compounds of the Invention Compounds of the invention can be prepared according to Reaction Scheme 1 wherein R, R ₂ , R ₃ , R ₄ , X,

Z and n are as defined above and R 11 is -R 6 -alkyl, -R 6 -aryl, -R 6 -heteroaryl or -R 6 -heterocyclyl, wherein R 6 is as defined above.

In step (1) of Reaction Scheme I, 1H-imidazo [4,5-c] quinolin-1-alcohol of formula X is alkylated with a halide of formula XI to give 1H-imidazo [4,5-c] quinolin-1-yl- of an ether of formula XII. The alcohol of formula (X) is reacted with sodium hydride in a suitable solvent such as N, N-dimethylformamide to form alkoxides. Alternatively, the alkoxide may be formed by adding the alcohol to a biphasic mixture of aqueous 50% sodium hydroxide and an inert solvent such as dichloromethane in the presence of a phase transfer catalyst such as benzyltrimethylammonium chloride. The alkoxide is then mixed with the halide. The reaction may take place at room temperature.

Many compounds of formula (X) are known, see, for example, Gerster, U.S. Patent 4,689,338, others can be readily prepared by known synthetic procedures, see, for example, Gerster et al., U.S. Patent 5,605,899 and Gerster, U.S. Patent 5,175,296.

Many halides of formula XI are commercially available, others can be readily prepared using known synthetic methods.

In step (2) of Reaction Scheme I, the 1 H -imidazo [4,5- c] quinolin-1-yl ether of formula 40 is oxidized to give 1 H -imidazo [4,5- c] quinoline-5 H -oxide of the formula (XIII) with a conventional oxidizing agent capable of forming N-oxides. Preferably, a solution of the compound of formula XII in chloroform is oxidized with 3-chloroperoxybenzoic acid at room temperature.

In step (3) of Reaction Scheme I, the 1H-imidazo [4,5-c] quinoline-5H-oxide of formula XIII is aminated to give the 1H-imidazo [4,5-c] quinolin-4-amine of general formula of formula XIV, which is a subgroup of formula I,

- 7 GB 303462 B6

Step (3) comprises (i) reacting a compound of formula XIII with an acylating agent and then (ii) reacting the product with an amination agent.

Part (i) of step (3) comprises reacting the V-oxide of formula XIII with an acylating agent. Suitable acylating agents include alkyl or arylsulfonyl chlorides (e.g., benzenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred. Most preferred is t-toluenesulfonyl chloride.

Part (ii) of step (3) comprises reacting the product of part (i) with an excess of the amination agent. Suitable amination agents include ammonia (e.g. in the form of ammonium hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate). Ammonium hydroxide is preferred. The reaction is preferably carried out by dissolving the V-oxide of formula XIII in an inert solvent such as dichloromethane, adding the amination reagent to the solution, and then slowly adding the acylating agent. The product or a pharmaceutically acceptable salt thereof may be isolated by conventional methods.

Alternatively, step (3) can be carried out (i) by reacting the V-oxide of formula XIII with an isocyanate and then (ii) hydrolyzing the resulting product.

Part (i) comprises reacting the N-oxide with an isocyanate, wherein the isocyanate group is attached to the carbonyl group. Preferred isocyanates include trichloroacetyl isocyanate and aroyl isocyanates such as benzoyl isocyanate. The reaction of the isocyanate with the V-oxide is carried out under substantially anhydrous conditions by adding the isocyanate to a solution of the N -oxide in an inert solvent such as chloroform or dichloromethane.

Part (ii) comprises hydrolyzing the product of part (i). The hydrolysis can be carried out by conventional methods such as heating in the presence of water or a lower alkanol, optionally in the presence of a catalyst such as an alkali metal hydroxide or a lower alkoxide. The product or a pharmaceutically acceptable salt thereof can be isolated by conventional procedures.

Reaction Scheme I

Compounds of the invention can be prepared according to Reaction Scheme II where R, R _2, R 4, R _7, R _U, X, n are as defined above and BOC is adverts-butoxycarbonyl.

-8EN 303462 B6

In step (1) of Reaction Scheme II, the amino group of the amino alcohol of formula XV is protected with a tert-butoxycarbonyl group. A solution of the amino alcohol in tetrahydrofuran is treated with di-tert-butyl di-carbonate in the presence of a base such as sodium hydroxide,

Many amino alcohols of formula XV are commercially available, others can be readily prepared using known synthetic methods.

In step (2) of Reaction Scheme II, a protected amino alcohol of formula XVI is converted to an iodide of formula XVII. To a solution of triphenylphosphine and imidazole in dichloromethane was added iodine; then a solution of protected amino alcohol of formula XVI in dichloromethane is added. The reaction may be carried out at room temperature.

In step (3) of Reaction Scheme II, the 1H-imidazo [4,5-c] quinolin-1-yl alcohol of formula X is alkylated with an iodide of formula XVII to give 1H-imidazo [4,5-c] quinoline 1-yl ether of formula XVIII. The alcohol of formula X is reacted with sodium hydride in a suitable solvent, such as N-dimethyl forms i d, to form an alkoxide. The iodide is added to the alkoxide solution at room temperature. After the addition is complete, the reaction is stirred at an elevated temperature (about 100 ° C).

In step (4) of Reaction Scheme II, the 1 H -imidazo [4,5- c] quinolin-1-yl ether of formula XVIII is oxidized to give 17 H -imidazo [4,5- c] quinoline-5 N -oxide of formula XIX using a conventional oxidizing agent capable of forming N -oxides. A solution of the compound of formula (XVIII) in chloroform is preferably oxidized using 3-chloroperoxybenzoic acid at room temperature.

In step (5) of Reaction Scheme II, the 1 H -imidazo [4,5- c] quinoline-5 H -oxide of formula XIX is aminated to give 1 H -imidazo [4,5- c] quinoline-4- of the amine XX.

Step (5) comprises (i) reacting a compound of formula XIX with an acylating agent and then (ii) reacting the product with an amination agent.

Part (i) of step (5) comprises reacting the oxiduΛ -oxide of formula XIX with an acylating agent. Suitable acylating agents include alkyl or arylsulfonyl chlorides (e.g., benzenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride), and arylsulfonyl chlorides are preferred. Most preferred is p-toluenesulfonyl chloride.

Part (ii) of step (5) comprises reacting the product of part (i) with an excess of the amination agent. Suitable amination agents include ammonia (e.g., in the form of ammonium hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate). Ammonium hydroxide is preferred. The reaction is preferably carried out by dissolving the N -oxide of formula XIX in an inert solvent such as dichloromethane or 1,2-dichloroethane with heating if necessary; adding the amination agent to the solution, and then slowly adding the acylating agent. Alternatively, the reaction may be carried out in a sealed pressure vessel at elevated temperature (85-100 ° C).

In step (6) of Reaction Scheme II, the protecting group is removed by hydrolysis under acidic conditions to provide the 1 H -imidazo [4,5- c] quinoline-4-amine of Formula XXL The compound of Formula XX is preferably treated with hydrochloric acid / ethanol at at room temperature or with gentle heating.

In step (7) of Reaction Scheme II, the 1H-imidazo [4,5-c] quinolin-4-amine of formula XXI is converted to the amide of formula XXII, which is a subgroup of formula 1, using conventional synthetic methods.

For example, a compound of formula XXI can be reacted with an acid chloride of formula RiiC (O) Cl. The reaction may be carried out by adding a solution of the acid chloride in a suitable solvent such as dichloromethane or 1-methyl-2-pyrrolidinone to a solution of the compound of formula XXI at room temperature.

Alternatively, a compound of formula XXI may be reacted with an acid of formula RnCOOH. The reaction may be carried out at room temperature in a solvent such as dichloromethane or pyridine using a conventional coupling reagent such as 1,3-dicyclohexylcarbodiimide or 1- [3 (dimethylamino) propyl] -3-ethylcarbodiimide. The product or a pharmaceutically acceptable salt thereof can be isolated by conventional procedures.

Reaction Scheme II

HIM

(D / BOC)

HO — R — N - (XVI) (XV)

R _T / BOC

I- (XVII) R ₇

Compounds of the invention can be prepared according to Reaction Scheme III, wherein R, R ₂ , R ₄ , R 6, Rh, X and n are as defined above and BOC is tert-butoxycarbonyl.

In step (1) of Reaction Scheme III, the amino group of the amino alcohol of formula XXIII is protected with a tert-butoxycarbonyl group. A solution of the amino alcohol in tetrahydrofuran is treated with di-tert-butyl dicarbonate in the presence of a base such as sodium hydroxide.

Many amino alcohols of formula XXIII are commercially available, others may be prepared using known synthetic methods.

In step (2) of Reaction Scheme III, the protected amino alcohol XXIV is converted to the methanesulfonate XXV. A solution of the compound of formula XXIV in a suitable solvent such as dichloromethane is treated with methanesulfonyl chloride in the presence of a base such as triethylamine. The reaction can be carried out at reduced temperature (0 ° C).

In step (3a) of Reaction Scheme III, the methanesulfonate of formula XXV is converted to the azide of formula XXVI. Sodium azide is added to a solution of the compound of formula XXV in a suitable solvent such as N, N -dimethylformamide. The reaction can be carried out at an elevated temperature (80 to 100 ° C).

In step (3b) of Reaction Scheme III, a compound of formula XXVI is alkylated with a halide of formula Hal-R? to obtain a compound of formula XXVII. For compounds in which R _{7 is} hydrogen, this step is omitted. The compound of formula XXVI is reacted with sodium hydride in a suitable solvent, such as Μ AM and methyl forms, to form an anion and then combined with a halide. The reaction can be carried out at room temperature.

In step (4) of Reaction Scheme III, an azide of formula XXVI or XXVII is reduced to give an amine of formula XXVIII. The reduction is preferably carried out using a conventional heterogeneous hydrogenation catalyst such as palladium on carbon. The reaction may conveniently be carried out in a Parr reactor in a suitable solvent such as methanol or isopropanol.

In step (5) of Reaction Scheme III, 4-chloro-3-nitroquinoline of formula XXIX is reacted with an amine of formula XXVIII to give a 3-nitroquinoline of formula XXX. The reaction may be carried out by adding an amine of formula XXVIII to a solution of a compound of formula XXIX in a suitable solvent such as dichloromethane in the presence of a base such as triethylamine.

Many quinolines of formula XXIX are known compounds or can be prepared using known synthetic compounds, see, for example, U.S. Patent 4,689,338, and references cited therein.

In step (6) of Reaction Scheme III, the 3-nitroquinoline of formula XXX is reduced to give the 3-aminoquinoline of formula XXXI. The reduction is preferably carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon. The reaction may conveniently be carried out in a Parr reactor in a suitable solvent such as toluene.

In step (7) of Reaction Scheme III, a compound of Formula XXXI is reacted with a carboxylic acid or equivalent thereof to give the 1H-imidazo [4,5-c] quinoline of Formula XVIII. Suitable carboxylic acid equivalents include orthoesters and 1,1-dialkoxy-35 alkyl alkanoates. The carboxylic acid or equivalent is selected to provide the desired R ₂ substituent in the compound of Formula XVIII. For example, triethyl orthoformate will provide a compound wherein R ₂ is hydrogen, and triethyl orthovalerate will provide a compound wherein R ₂ is butyl. The reaction may be carried out in the absence of a solvent or in an inert solvent such as toluene. The reaction proceeds with adequate heating to remove alcohol or water that is formed as a by-product of the reaction. Preferably, a catalyst such as pyridine hydrochloride may be used.

Alternatively, step (7) can be carried out by (i) reacting a compound of formula XXXI with an acyl halide of formula R ₂ C (O) Cl or R ₂ C (O) Br and then (ii) cyclization.

In part (i), the acyl halide is added to a solution of the compound of formula XXXI in an inert solvent such as acetonitrile or dichloromethane. The reaction may be carried out at room temperature or at a reduced temperature.

In part (ii), the product of part (i) is heated in an alcoholic solvent in the presence of a base. Preferably, the product of part (i) is refluxed in ethanol in the presence of excess triethylamine or heated with methanolic ammonia.

Steps (8), (9), (10) and (11) are performed in the same manner as steps (4), (5), (6) and (7) of Reaction Scheme II.

-IICZ 303462 B6

Reaction Scheme III

_XO-HO-R-NH2 (ΧΧ1Π) (1)

HO-XOR - N ⁴ H (XXIV) / BOC

Í2)

₃ - xo (XXVI)

Rr - N ⁴ H / BOC (3a)

SOXO — R — N ^ ^{BOC 4} H

(XXV)

NXO — R — New ^BOC (XXVII) ^R 7

HjN-XO — R ₄ —N ^BOCl 4 _χ (XXVIII) R _T0

«*

(8)

- I2 GB 303462 B6

Compounds of the invention may also be prepared according to Reaction Scheme IV wherein R, R 1, R ₂ , X and _n are as defined above.

In Reaction Scheme IV, a 4-amino-1H-imidazo [4,5-c] quinolin-1-yl alcohol of formula XXXII is alkylated with a halide of formula XXXIII to give 1H-imidazo [4,5-c] The alcohol of formula XXXII is reacted with sodium hydride in a suitable solvent such as N-dimethylformamide to form an alkoxide. The halide is then added to the reaction mixture. The reaction can be carried out at room temperature or with gentle heating (5050 ° C), if desired. The product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.

Many compounds of formula XXXII are known, see, for example, Gerster, U.S. Pat. No. 4,689,338 and Gerster et al., U.S. Pat. others can be readily prepared by known synthetic procedures, see, for example, Andre et al., U.S. Patent 5,678,727; Gerster, U.S. Patent No. 5,175,296; Nikolaides et al., Patent 5,395,937; and Gerster et al., Patent 5,741,908, the disclosure of which is incorporated herein by reference.

Many halides of formula XXXIII are commercially available, others can be readily prepared by known synthetic methods.

Reaction Scheme IV

Compounds of the invention can be prepared according to Reaction Scheme V wherein R, R ₂ , R ₄ , R 7, 25 R 11, X and _n are as defined above.

In step (1) of Reaction Scheme V, the 1H-imidazo [4,5- a] quinolin-4-amine of formula XXI is reduced to give 6,7,8,9-tetrahydro-1H-imidazo [4] 5-c] quinolin-4-amine of formula XXXV. The reduction is preferably carried out by suspending or dissolving the compound of formula XXI in trifluoroacetic acid, adding a catalytic amount of platinum oxide and then hydrogenating. The reaction may conveniently be carried out in a Parr reactor.

Step (2) is performed in the same manner as step (7) in Reaction Scheme II to provide 6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinolin-4-amine of formula XXXV, which is below a group of formula II. The product or a pharmaceutically acceptable salt thereof may be isolated by conventional methods.

- 13GB 303462 B6

Reaction Scheme

The compound of the invention can be prepared according to Reaction Scheme VI wherein R, R _b, R ₂ , X and _n are as defined above.

In Reaction Scheme VI, a 4-amino-6,7,8,9-tetrahydro-17 H -imidazo [4,5- c] quinolin-1-yl alcohol of formula XXXVI is alkylated with a halogen of formula XXXIII to give 6 7,8,9-tetrahydro-1H-imidazo [4,5-c] quinolin-4-amine of formula IL

The alcohol of formula XXXVI is reacted with sodium hydride in a suitable solvent such as N, N- or methyl forms i d to form an alkoxide. Halo id is then added to the reaction mixture. The reaction can be carried out at room temperature or with gentle heating (- 50 ° C), if desired. The product or a pharmaceutically acceptable salt thereof may be isolated by conventional methods.

Many 6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinolines of formula XXXVI are known, see, for example, Nikolaides et al., U.S. Patent 5,352,784; others can be prepared by known synthetic methods, see, for example, Lindstrom, U.S. Patent 5,693,811; the disclosure of which is incorporated herein by reference.

Reaction Scheme VI NH, Λ -N + Hal- -N X (XXXVI) OH (XXXlll)

The invention also provides novel compounds useful as intermediates in the synthesis of compounds of formulas I and II. These intermediate compounds have structural formulas III-V, described in more detail below.

One group of intermediate compounds has the general formula III:

- 14GB 303462 B6 where:

X is -CHR ₅ - -CHR <-alkyl-, or -CHR ₅ -alkenyl-;

R 1 is selected from the group consisting of:

-R ₄ -CR ₃ -ZR ₆ -alkyl;

-R ₄ -CR ₃ -ZR ₆ -alkenyl;

10 -R ₄ -CR ₃ -ZR ₆ -aryl;

-R ₄ -R ₃ -ZR ₆ -heteroary I;

-R ₄ -CR ₃ -ZR ₆ -heterocyclyl;

-R ₄ -CR ₃ -Z-H;

-R ₄ -NR ₁ -CR 3 -R 6 -alkyl;

-R ₄ -NR 7 -CR ₃ -R ₆ -alkenyl;

—R4 —N R7 — CR3 — Rfi — aryl 1;

-R 4 -NR 8 -CR 3 -R 6 -heteroaryl;

-R ₄ -NR -CR3 _{r-ro-heterocyclyl;} and

-R ₄ -NR ₆ CR ₃ -R ₈ ;

each Z is independently -NR 5 -, -O- or -S-;

R ₂ is selected from the group consisting of

- hydrogen;

- alkyl;

alkenyl;

-aryl;

- heteroaryl;

- heterocyclyl;

alkyl-Y-alkyl;

- alkyl-Y-alkenyl;

alkyl-Y-aryl; and

- alkyl or alkenyl substituted with one or more substituents selected from the group consisting of:

-OH;

- halogen;

-N (R ₅ ) ₂ ;

- CO - N (R ₅ ) ₂ ;

-CO-C _1-10 alkyl;

-CO-OC _1-10 alkyl;

-N ₃ ;

- 15 GB 303462 B6

-aryl;

- heteroaryl;

- heterocyclyl;

- CO-aryl; and

C 1 -C 5 -aryl;

each R ₃ is = O or = S;

each R 4 is independently alkyl or alkenyl, which may be interrupted by one or more -O groups;

each R ₅ is independently H or C _1-10 alkyl;

R 6 is a bond, alkyl or alkenyl, which may be interrupted by one or more -O- groups;

R ₇ is H, _{C] O} alkyl or arylalkyl; or R 4 and R ₇ may combine to form a ring;

R ₈ is H or C | _i _O alkyl; or R ₇ and R ₈ may combine to form a ring; each Y is independently -O- or -S (O) 0-2-;

n is 0 and 4; and each R present is independently selected from the group consisting of _{C) O} alkyl, C] _i ₀ alkoxy, hydroxy, halogen and trifluoromethyl;

or a pharmaceutically acceptable salt thereof.

Another group of intermediates is described by formula IV:

X is -CHR5-, -CHR5alkyl- or -CHR-alkenyl-; Ri is selected from the group consisting of:

R ₄ -C R 7 -R ₆ -alkyl;

- R ₄ —CR ₃ -Z- R 8 -a 1 ken y I;

-R ₄ -CR ₁ -ZR ₆ arvl:

-R ₄ -C R y -Z-R ₆ -heteroaryl; -R ₄ -CR ₃ -ZR 8 -heterocyclyl;

- 16GB 303462 B6

-Kt-CR ₃ -ZH;

-R ₄ -NR ₇ -CR ₃ -R ₆ -alkyl -R ₄ -NR 7 -C 6 R ₃ -R ₆ -alkenyl; -R ₄ -NR ₇ -CR ₃ -R ₆ -aryl;

-R 4 -NR 7

-CR 5 -R 6 -heteroaryl; -R 4 -NR 7 -CR ₃ -R 6 -heterocyclyl; and -R 4 -NR ₇ -CR ₃ R _8;

each Q is independently -NR 5 -, -O-;

each R ₃ is = O or = S;

each R ₄ is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups;

each R ₅ is independently H or C 1-10 alkyl;

R 6 is a bond, alkyl or alkenyl, which may be interrupted by one or more -O-groups;

R ₇ is C ₁ -C ₁₀ alkyl or arylalkyl; or R ₇ can combine to form a ring;

R ₈ is H or C 1-10 -alkyl or arylalkyl; or R 4 and R ₇ may combine to form a ring; n is 0 to 4; and each R is present independently selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, hydroxy, halogen and trifluoromethyl; or a pharmaceutically acceptable salt thereof.

Another group of intermediate compounds has the general formula V:

where:

X is -CHR ₅ - -CHR ₅ -alkyl- or -CHR _; -alkenyl-;

R ₂ is selected from the group consisting of:

- hydrogen;

- 17 GB 303462 B6

-alkyl;

alkenyl;

-aryl;

- heteroaryl;

- heterocyclyl;

alkyl-Y-alkyl;

- alkyl-Y-alkenyl;

alkyl-Y-aryl; and

- alkyl or alkenyl substituted with one or more substituents selected from the group consisting of:

-OH;

- halogen;

-N (R ₅ ) ₂ ;

₁₅ -CO-N (R ₅ ) ₂ ;

CO-Cnoalkyl;

- CO-O-C | _{_] 0} alkyl;

-N ₃ ;

-aryk

- heteroaryl;

- heterocyclyl;

- CO-aryl; and

- CO-heteroaryl;

each R 4 is independently alkyl or alkenyl, which may be interrupted by one or more -O groups;

R? is H, C] 1 _O alkyl or aralkyl; or R ₄ and R ₇ may combine to form a ring;

each Y is independently -O- or -S (O) o ₂ -;

n is 0 and 4; and each R 1 present is independently selected from the group consisting of C 1-6 alkyl, C _1-10 alkoxy, hydroxy 35, halogen, trifluoromethyl;

or a pharmaceutically acceptable salt thereof.

As used herein, the terms "alkyl", "alkenyl" and the prefix "alk-" include straight and branched chain groups and cyclic groups, ie, cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain 1 to 20 carbon atoms, with alkenyl groups containing 2 to 20 carbon atoms. Preferred groups have a total number of up to 10 carbon atoms. The cyclic groups may be monocyclic or polycyclic and preferably have from 3 to 10 carbon atoms in the ring. Typical cyclic groups include cyclopropyl, cycliopropylmethyl, cyclopentyl, cyclohexyl and adamantyl.

- 18GB 303462 B6

In addition, the alkyl and alkenyl moieties of the -X- groups may be unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, aryl 1, heteroaryl 1 and heterocyclylalkyl.

The term "haloalkyl" includes groups which are unsubstituted by one or more halogen atoms, including perfluorinated groups. However, these are also groups that contain the prefix "halo -". Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl and the like.

The term "aryl" as used herein includes carboxyl aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl.

The term "heteroaryl" includes aromatic rings or ring systems that contain at least one ring heteroatom (eg, O, S, N).

Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, , naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl and so on.

"Heterocyclyl" includes non-aromatic rings or ring systems containing at least one ring heteroatom (eg, O, S, N) and includes all fully saturated and partially unsaturated derivatives of the above heteroaryl groups.

Typical heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholine and nineridinyl. ninerazinvl. thiazolidinyl. thmidazolidinyl, isothiazolidinyl and so forth.

The aryl, heteroaryl and heterocyclyl compounds may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylthio, arylalkoxy, aryl lathio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaryl alkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenyl carbonyl, alkoxy carbonyl, haloalkyl carbonyl, haloalkoxy, haloalkoxy, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, alkanoyloxy, alkanoylthio, alkanoylamino, aroyloxy, aroylthio, aroylamino, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, arylsulfonyl , arylalkylsulfonylamino, alkylcar bonylamino, alkenyl carbonylamino, arylaminocarbonylamino, arylalkylcarbonylamino, heteroarylaminocarbonylamino, heteroarylcarbonylamino, heteroarylsulfonylamino, heteroarylalkylsulfonylamino, alkylaminocarbonylamino, alkenylaminocarbonylamino, arylamininocarbonylamino, arylamininocarbonylamino, arylamininocarbonylamino, arylaminocarbonylamino, arylaminocarbonylamino in the case of heterocycle, oxo.

When some other groups are referred to as "substituted" or "optionally substituted", these groups may also be substituted by one or more of the above-mentioned substituents.

Typically, certain substituents are preferred. For example, preferred R1 groups include -R 4 CR-ZR ₆ -alkyl and -R 4 -CR ₃ -Z-R ₆ -aryl, wherein the alkyl and aryl groups may be unsubstituted or substituted; R ₃ is preferably = O; R4 is preferably ethylene or n-butylene; and Z is preferably -NR 5 -. Preferably, no R substituents are present (i.e. n is 0). Preferred R ₂ groups include alkyl groups having 1 to 4 carbon atoms (ie, methyl, ethyl, propyl, isopropyl, p -butyl, sec -butyl, isobutyl and cyclopropylmethyl), methoxyethyl and ethoxymethyl. For substituted groups such as substituted alkyl or substituted aryl groups, preferred substituents include halogen, nitrile, methoxy, trifluoromethyl and trifluoromethoxy. One or more

Of these preferred substituents, if present, may be present in the compounds of the invention in any combination.

The invention includes the compounds described herein in any pharmaceutically acceptable form, including isomers (eg, diastereomers and enantiomers), salts, solvates, polymorphs, and so on. In particular, when the compound is optically active, the invention explicitly includes each of the enantiomers of the compound as well as racemic mixtures of these enantiomers.

Pharmaceutical preparations and biological activity

The pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of the invention as described above in combination with a pharmaceutically acceptable carrier.

The term "therapeutically effective amount" means an amount of a compound sufficient to produce a therapeutic effect, such as cytokine induction, anti-tumor effect, and / or antiviral activity.

Although the exact amount of active compound used in a pharmaceutical composition will vary according to circumstances known to those skilled in the art, such as the physical and chemical nature of the compound, the type of carrier and the dosage regimen chosen, the compositions of the invention are expected to contain sufficient active ingredient to provide a dosage. about 100 ng / kg to about 50 mg / kg, preferably about 10 µg / kg to 5 mg / kg of the subject compound.

Any conventional dosage forms such as tablets, caramels, parenteral compositions, syrups, creams, ointments, aerosol compositions, transdermal patches, transmucosal patches and so on can be used.

The compounds of the invention may be administered as a single therapeutic agent in a treatment regimen or the compounds of the invention may be administered in combination with one or more additional active agents, including other immune response modifiers, anti-viral agents, antibiotics, etc.

The compounds of the invention in tests performed according to the tests below have shown that they induce the production of certain cytokines. These results suggest that the compounds are effective as immune response modifiers that can regulate the immune response in a variety of ways, making them useful for treating various diseases.

Cytokines whose formation can be induced by administration of the compounds of the invention generally include Interferon-α (IFN-α) and / or tumor necrosis factor-α (TNF-α) as well as certain interleukins (IL). Cytokines whose biosynthesis can be induced by the compounds of the invention include

IFN-α, TNF-α, IL-1, IL-6,1L-10 and IL-12, and many other cytokines.

Among other effects, these and other cytokines can inhibit the production of viruses and tumor cell growth, making these compounds useful for the treatment of viral diseases and tumors,

Accordingly, the invention provides a method of inducing cytokine biosynthesis in an animal, comprising administering to the animal an effective amount of a compound or composition of the invention.

It has been discovered that certain compounds of the invention preferentially induce IFN-α expression in sets of hemato-poetic cells, such as PBMCs (peripheral blood mononuclear cells), containing pDC2 cells (type 2 precursor dendritic cells) without concomitant formation of significant levels of inflammatory cytokines.

In addition to the ability to induce cytokine production, the compounds of the invention affect other aspects of the immune response itself. For example, the activity of natural killer buffers may be stimulated, an effect that can be attributed to the induction of cytokines. The compounds may also activate macrophages that in turn stimulate nitric oxide secretion and production of other cytokines. In addition, the compounds may cause B-lymphocyte proliferation and differentiation.

The compounds of the invention also have an effect on the secondary immune response. For example, although a direct effect on T cells or on the direct induction of T cell cytokines is unlikely to occur, administration of these compounds indirectly induces the production of TH1 cells by IFN-γ (Th1) and TH2 cells by cytokines IL-4, IL- 5 and IL-13 (Th2) are inhibited. This effect means that the compounds are useful in the treatment of diseases where an increase in Th1 response and / or a decrease in Th2 response is desirable.

Given the ability of the compounds of the invention to inhibit the Th2 immune response, the compounds are expected to be useful in the treatment of atopic diseases such as atopic dermatitis, asthma, allergies, allergic rhinitis; systemic lupus erythematosus; as a vaccine adjuvant for cell-mediated immunity; and optionally as a treatment for recurrent fungal diseases and chlamydia.

The immune response modifying compounds render them useful for the treatment of a wide variety of diseases. Because of their ability to induce the production of cytokines such as IFN-α and / or TNF-α, the compounds are particularly useful for the treatment of viral diseases and tumors.

This immunomodulatory effect suggests that the compounds of the invention are useful in the treatment of diseases such as, but not limited to, viral diseases including genital warts; common warts; warts on the feet, hepatitis B, hepatitis C, herpes simplex virus type 1 and iypu 2, iiiuiu & kenya coniagiózr. ;; varriola major; ΗΪΥ; CMY; YZV; rhmovirus; adenoviruses; flu; parainfluenza; Intraepithelial neoplasia such as cervical intrapepithelial neoplasia; human papillomavirus (HPV) and associated neoplasia; fungal diseases such as candida, aspergillus and cryptococcal meningitis; cancer diseases, e.g., basocellular carcinoma, hair cell leukemia, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgkins lymphoma, T-cell skin lymphoma and other cancers; parasitic diseases such as pneumocystosis, crypto spore idiosis, histoplasmosis, toxoplasmosis, trypanosomal infections and leishmaniasis; and bacterial infections such as tuberculosis and mycobacterium avium.

Other diseases or conditions that can be treated with the compounds of the invention include radiation keratosis; eczema; eosinophilia; essential thrombocythaemia; lepru; multiple sclerosis; Ommen's syndrome; discoid lupus; Bowen's disease; bowenoid papulosis; alopecii areata; inhibition of colloidal formations after surgery and other types of postoperative scars.

In addition, these compounds could improve or stimulate wound healing, including chronic wounds. The compounds may be useful in the treatment of opportunistic infections and tumors that occur following suppression of cell-mediated immunity, for example in transplant patients, cancer patients or HIV patients.

The amount of compound effective to induce cytokine biosynthesis is an amount sufficient to induce one or more cell types, such as monocytes, macrophages, dendritic cells, and B-cells, to produce an amount of one or more cytokines such as IFN-α, TNF-α, IL-1, IL-6, IL-10 and IL-12, which increase above baseline of these cytokines.

The exact amount will vary according to factors known in the art, but is expected to be a dose of about 100 ng / kg to 50 mg / kg, preferably about 10 gg / kg to 5 mg / kg.

The invention also provides a method of treating a viral infection in an animal and a method of treating a cancer in an animal, comprising administering to the animal an effective amount of a compound or composition of the invention.

-21 GB 303462 B6

An amount effective for treating or inhibiting a viral infection is an amount that will alleviate one or more manifestations of a viral infection, such as viral lesions, viral infection, virus production rate, and mortality compared to untreated control animals,

The exact amount will vary depending on factors known in the art, but is expected to be a dose of about 100 ng / kg to 50 mg / kg, preferably about 10 µg / kg to 5 mg / kg.

The amount of compound effective to treat cancer is an amount that will cause a reduction in the size of the tumors or the number of tumor foci. Again, the exact amount will vary depending on factors known in the art, but it is expected that it will be about

100 ng / kg to 50 mg / kg, preferably about 10 µg / kg to 5 mg / kg.

The invention is further described by the following examples, which are provided by way of illustration only and are not intended to be limiting in any way.

Examples

In the examples below, some compounds are purified by semi-preparative HPLC. Two different methods were used as described below.

Method A

This method used the A-1090 Gilson-6 equipped with 900 series of intelligent interfaces. Semi-preparative HPLC fractions were analyzed by LC-APCI / MS and the appropriate fractions were combined and lyophilized to give the trifluoroacetate salt of the title compound.

Column: Microsorb C18 column, 21.4 x 250 mm, 8 µm particle size, 60 Å (6 nm) cavity; flow rate: 10 ml / min; gradient elution from 2 to 95% B in 25 min, hold at 95% B for 5 min, where A = 0.1% trifluoroacetic acid / water and B = 0.1% trifluoroacetic acid / acetonitrile, peak detection at 254 nm for the fraction trigger file.

Method B

This method used the Waters Fraction Lynx automated cleaning system. The semi-preparative HPLC fractions were analyzed by Micromass LC-TOFMS and the appropriate fractions were combined and centrifuged to give the trifluoroacetate salt of the title compound. The composition was confirmed by 1 H NMR spectroscopy,

Column: Phenomenex Luna 08 (2), 10 x 50 mm, particle size 5 µm; cavities 100 A (10 nm); flow rate: 25 ml / min; gradient elution from 5 to 65% B in 4 min, then 65 to 95% B in 0.1 min, then hold at 95% B 0.4 min, where A = 0.05% trifluoroacetic acid / water aB = 0.05% trifluoroacetic acid / acetonitrile, fraction collection by mass-selective triggering.

Example 1 1- [2- (2-Aminoethoxy) ethyl] -2-butyl-1H-imidazo [4,5-c] quinolin-4-amine

O

NH.

Part A

A solution of 2- (2-aminoethoxy) ethanol (29.0 g, 0.276 mol) in 180 mL of tetrahydrofuran (THF) under nitrogen was cooled to 0 ° C and treated with 140 mL of 2N NaOH solution. A solution of di-tert-butyldi carbonate (60.2 g, 0.276 mol) in 180 ml THF was then added dropwise to the rapidly stirred solution over 1 hour. The reaction mixture was then allowed to warm to room temperature and stirred for an additional 18 hours. THF was removed under reduced pressure and the remaining aqueous suspension was adjusted to pH 3 by addition of 150 mL of 1 M H ₂ SO ₄ solution. The suspension was then extracted with ethyl acetate (300 mL,

100 mL) and the combined organic layers were washed with water (2x) and brine. The organic portion was dried over Na ₂ SO ₄ and concentrated to give tert-butyl-2- (2-hydroxyethoxy) ethylcarbamate 15 as a colorless oil (47.1 g).

Λ '. r>

l_>

A rapidly stirred solution of tert-butyl 2- (2-hydroxyethoxy) ethylcarbamate (47.1 g, 0.230 mol) in 1 L of anhydrous CH ₂ Cl ₂ was cooled to 0 ° C under nitrogen and treated with triethylamine (48.0 mL). , 0.345 mol). Methanesulfonyl chloride (19.6 mL, 0.253 mol) was then added dropwise over 30 minutes. The reaction mixture was then allowed to warm to room temperature and stirred for an additional 22 hours. The reaction was quenched by the addition of 500 mL of saturated NaHCO ₃ solution and the organic layer was separated. The organic phase was then washed with water (3 x 500 mL) and brine. The organic portion was dried over Na ₂ SO ₄ and concentrated to give 2- {2 - [(tert-butoxycarbonyl) amino] ethoxy} ethyl methanesulfonate as a brown oil (63.5 g).

PartC

A stirred solution of 2- {2 - [(tert-butoxycarbonyl) amino] ethoxy} ethyl methanesulfonate (63.5 g, 0.224 mol) in 400 mL of N, N-dimethylformamide (DMF) was treated with NaN ₃ (16.1 g, 0.247 mol) ) and the reaction mixture was heated to 90 ° C under nitrogen. After 5 hours, the solution was cooled to room temperature and treated with 500 mL cold H ₂ O. The reaction mixture was then extracted with Et ₂ O (3 x 300 mL). The combined organic extracts were washed with H ₂ O (4 x 100 mL) and brine (2x

100 ml). The organic portion was dried over MgSO ₄ and concentrated to give 52.0 g of tert-butyl 2- (2-azidoethoxy) ethylcarbamate as a light brown oil.

Part D

A solution of tert-butyl 2- (2-azidoethoxy) ethylcarbamate (47.0 g, 0.204 mol) in MeOH was treated with 4 g of 10% Pd on carbon and shaken under hydrogen (3 kg / cm ² ) for 24 hours. The solution was then filtered through a total pad and concentrated to give 35.3 g of crude tert-butyl 2 (2-aminoethoxy) ethylcarbamate as a colorless liquid which was used without further purification.

-? 3 CZ 303462 B6

Part E

A stirred solution of 4-chloro-3-nitroquinoline (31.4 g, 0.151 mol) in 500 mL of anhydrous CH ₂ Cl ₂ under nitrogen was treated with triethylamine (43 mL, 0.308 mol) and tert-butyl-2- (2 "aminoethoxy) ) with ethyl carbamate (0.151 mol). After stirring overnight, the reaction mixture was washed with water (2 x 300 mL) and brine (300 mL). The organic portion was dried over Na ₂ SO ₄ and concentrated to give a bright yellow solid. Recrystallization from ethyl acetate / hexanes gave 43.6 g of tert-butyl-2- {2 [(3-nitroquinolin-4-yl)]. amino] ethoxy} ethylcarbamate in the form of bright yellow crystals.

Part F

A solution of tert-butyl 2- {2 - [(3-nitroquinolin-1-yl) amino] ethoxy} ethylcarbamate (7.52 g, 20.0 mmol) in toluene was treated with 1.5 g of 5% Pt on carbon and shaken. under H ₂ (3 kg / cm ² ) for 24 hours. The solution was then filtered through a celite pad and concentrated to afford 6.92 g of crude tert -butyl 2- {2 - [(3-aminoquinolin-1-yl) amino] ethoxy} ethylcarbanate as a yellow syrup.

Part G

A solution of tert-butyl 2- {2 - [(3-aminoquinolin-1-yl) amino] ethoxy} ethylcarbamate (3.46 g, 10.0 mmol) in 50 mL of toluene was treated with triethyl orthovalerate (2.5 mL, 14 mL). (5 mmol) and the reaction mixture was heated to reflux, then a 25 mg portion of pyridinium hydrochloride was added and reflux was continued for 4 hours. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was dissolved in 50 mL of CH ₂ Cl ₂ and washed with saturated NaHCO 3, H ₂ O and brine. The organic portion was dried over Na 2 SO ₄ and concentrated to give a green oil. The green oil was dissolved in 50 mL hot MeOH and treated with charcoal. The hot solution was filtered and concentrated to give 4.12 g of tert-butyl 2- [2- (2-butyl-1H-imidazo [4,5-c] quinolin-1-yl) ethoxy] ethylcarbamate as of yellow oil.

Part H

A solution of tert-butyl 2- [2- (2-butyl-1H-imidazo [4,5- c] quinolin-1-yl) ethoxy] ethylcarbamate (4.12 g, 10.0 mmol) in 50 mL of CH ₂ Cl ₂ was treated with 3-chloroperoxybenzoic acid (MCPBA, 77%, 2.5 g, 11.2 mmol). After stirring for 5 hours, the reaction mixture was treated with saturated NaHCO ₃ solution and the layers were separated. The organic portion was washed with water and brine, then dried over Na ₂ SO ₄ and concentrated to give 3.68 g of tert -butyl-2- [2- (2-butyl-5-oxido-1 H -imidazo [4,5- c]). [Quinolin-1-yl] ethoxy] ethylcarbamate as a light brown foam.

Part I

1- (2- (2-Butyl-5-oxido-1H-imidazo [4,5-c] quinolin-1-yl) ethoxy] ethylcarbamate tert-butyl solution (3.68 g, 8.60) mmol) in 100 mL 1,2-dichloroethane was heated to 80 ° C and treated with 10 mL concentrated NH ₄ OH solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (1.87 g, 9.81) over 10 minutes. The reaction mixture was then sealed in a pressure vessel and heating continued for 2 hours The reaction mixture was then cooled and treated with 100 mL of CH ₂ Cl ₂ The reaction mixture was then washed with water, 1% Na ₂ CO ₃ solution (3x) and The organic portion was dried over Na ₂ SO ₄ and concentrated to give 3.68 g of tert -butyl-2- [2- (4-amino-2-butyl) -1 H -imidazo [4,5- c] quinoline 1-yl) ethoxy] ethylcarbamate as a light brown foam.

Part J

7ez-t-butyl 2- [2- (4-amino-2-butyl-1H-imidazo [4,5- d] quinolin-1-yl) ethoxy] ethylcarbamate (3.68 g, 8 (60 mmol) was suspended in 20 mL of 2M HCl in EtOH and the mixture was heated to stirring with stirring

The reflux temperature. After 3 hours, the reaction mixture was concentrated to give a solid. The solid was triturated with hot EtOH (50 mL) and filtered to give 2.90 g of the product as the hydrochloride salt. The free base was formed by dissolving the hydrochloride salt in 50 mL H ₂ O and treated with 5 mL concentrated NH ₄ OH. The aqueous suspension was extracted with

CH7Cl2 (3 x 50 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give 1- [2- (2-aminoethoxy) ethyl] -2-butyl-1H-imidazo [4,5-c] quinolin-4-amine as of a tan powder.

MS 328 (M + H) \ 'H NMR (300 MHz, CDC1 ₃₎ δ 7.95 (d, J = 8.3 Hz, 1H); 7.83 (d, J = 8.4 Hz, 1H); 7.50 (m, 1H); 7.30 (tn, 1H); 5.41 (s, 2H); 4.69 (t, J = 5.6 Hz, 2H); 3.93 (t, J = 5.6 Hz, 2H); 3.39 (t, J = 5.1 Hz, 2H); 2.97 (t, J = 7.9 Hz, 2H); 2.76 (t, J = 5.1 Hz, 2H); 1.89 (m, 2H); 1.52 (m, 2H); 1.26 (br s, 2H); 1.01 (t, J = 7.3 Hz, 3H).

Example 2 1- [2- (2-Aminoethoxy) ethyl] -1 H -imidazo [4,5- c] quinolin-4-amine

Part A

A solution of tert-butyl 2- {2 - [(3-aminoquinolin-4-yl) amino] ethoxy} ethylcarbamate (6.92 g, 20.0 mmol) in 100 mL of toluene was treated with ethyl orthoformate (4.65 mL, 28.0 mmol) and the reaction mixture was heated to reflux. A 100 mg portion of pyridinium hydrochloride was then added and refluxing continued for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in 200 mL of CH ₂ Cl ₂ and washed with saturated NaHCO ₃ , H ₂ O and brine. The organic portion was dried over Na ₂ SO ₄ and concentrated to give a green oil. The green oil was dissolved in 200 mL hot MeOH and treated with 10 g of activated carbon.

The hot solution was filtered and concentrated to give 5.25 g of tert-butyl 2- [2- (1H-imidazo [4,5-c] quinolin-1-yl) ethoxy] ethylcarbamate as a pale yellow syrup.

Part B

Solution / tert butyk2- [2- (1 tf-imidazo [4,5-c] quinolin-l-yl) ethoxy] ethylcarbamate (5.25 g, 14.7 mmol) in 200 ml CH ₂ C1 ₂ was treated with MCPBA (77%, 3.63 g, 16.3 mmol). After stirring overnight, the reaction mixture was treated with saturated NaHCO ₃ solution and the layers separated. The organic portion was washed with water and brine, then dried over Na ₂ SO ₄ and concentrated to give 4.60 g of tert-butyl 2- [2- (5-oxido-1 H -imidazo [4,5- c] quinoline] 1-yl) ethoxy] 40 ethyl carbamate as a light brown foam.

Part C

A solution of tert-butyl 1-2- (2- (5-oxido-1H-imidazo [4,5-c] quinolin-1-yl) ethoxy] ethylcarbamate (4.60 g, 12.4 mmol) in 150 mL of 1,2-dichloroethane was heated to 80 ° C and treated with 10 mL of concentrated NH ₄ OH solution To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (2.71 g, 14.2 mmol) over 10 minutes. The reaction mixture was treated with an additional 2 mL

Concentrated NH ₄ OH solution and then sealed in a pressure vessel and heating was continued for 3 hours. The reaction mixture was then cooled and treated with 100 mL of CH ₂ Cl ₂ . The reaction mixture was then washed with water, 1% Na ₂ CO ₃ solution (3x) and brine. The organic portion was dried over Na ₂ SO ₄ and concentrated to give 4.56 g of tert-butyl-2- [2- (4-amino-1H-imidazo [4,5-c] 5-quinolin-1-yl) ethoxy] ethylcarbamate in the form of a light brown foam.

Part D

7-tert-Butyl 2- [2- (4-amino-1H-imidazo [4,5-c] quinolin-1-yl) ethoxy] ethylcarbamate (4.56 g, 10.3 mmol) was dissolved in 100 ml. mL of EtOH and treated with 30 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 3 hours, the reaction mixture was concentrated to give a solid. The solid was triturated with hot EtOH (100m) and filtered to give the product as the hydrochloride salt. The free base was formed by dissolving the hydrochloride salt in 50 mL H ₂ O and treated with 5 mL concentrated NH ₄ OH. The aqueous suspension was extracted with CH ₂ Cl ₂ (5 x 50 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give 1.35 g of 1- [2- (2-aminoethoxy) ethyl] -1 H -imidazo [4,5- c] quinolin-1-amine as a tan powder .

MS 272 (M + H) ^&lt; ^{+ &gt};;

1 H NMR (300 MHz, CDCl ₃ ) δ 7.98 (d, J = 8.2 Hz, 1H); 7.88 (s, 1H); 7.84 (d, J = 8.4 Hz, 1H); 7.54 (m, 1H); 7.32 (m, 1H); 5.43 (s, 2H); 4.74 (t, J = 5.2 Hz, 2H); 3.97 (t, J = 5.2 Hz, 2H); 3.42 (t, J = 5.1 Hz, 2H); 2.78 (t, J = 5.1 Hz, 2H); 1.10 (br s, 2H).

Example 3

1- [242-Aminoethoxy) ethyl] -2- (2-methoxyethyl) -1H-imidazo [4,5-c] quinoline-4-amine

Part A

Tert-Butyl] -2- {2 - [(3-aminoquinolin-4-yl) amino] ethoxy} ethylcarbamate solution (10.2 g,

29.5 mmol) in 250 mL of anhydrous CH ₂ Cl ₂ was cooled to 0 ° C and treated with triethylamine (4.18 mL, 30.0 mmol). Methoxypropionyl chloride (3.30 mL, 30.3 mmol) was then added dropwise over 5 minutes. The reaction was then warmed to room temperature and stirring was continued for an additional hour. The reaction mixture was then concentrated under reduced pressure to give an orange solid. This was dissolved in 250 mL of EtOH and 12.5 mL of triethylamine was added. The mixture was heated to reflux and stirred under nitrogen overnight. The reaction mixture was then concentrated to dryness under reduced pressure and treated with 300 mL of Et ₂ O. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give a brown solid. The solid was dissolved in 200 mL hot MeOH and treated with charcoal. The hot solution was filtered and concentrated to give 11.1 g of tert-butyl 2- {2- [2- (2-methoxyethyl) -1 H -imidazo [4,5- c] quinolin-1-yl) ethoxy] ethylcarbamate in form of yellow syrup.

-26EN 303462 B6

Part B

A solution of 2- {2- [2- (2-methoxyethyl) -1H-imidazo [4,5-c] quinolin-1-yl] ethoxy} ethyl tert-butyl (10,22 g, 24, 7 mmol) in 250 mL CHCl ₃ was treated with MCPBA (77%, 9.12 g,

40.8 mmol). After stirring for 30 minutes, the reaction mixture was washed with 1% Na ₂ CO ₃ solution (2 x mL) and brine. The organic layer was then dried over Na ₂ SO ₄ and concentrated to give 10.6 g of tert-butyl-2- {2- [2- (2-methoxyethyl) -5-oxido-1 H -imidazo [4], 5-quinolin-1-yl] ethoxy} ethylcarbamate as an orange foam which was used without further purification. io PartC

A solution of tert-butyl 2- {2- [2- (2-methoxyethyl) -5-oxo-1H-imidazo [4,5-c] quinolin-1-yl] ethoxy} ethyl carbamate (10.6 g) (24.6 mmol) in 100 mL of 1,2-dichloroethane was heated to 60 ° C and treated with 10 mL of concentrated NH ₄ OH solution. Into the rapidly stirred solution is added for

Solid p-toluenesulfonyl chloride (7.05 g, 37.0 mmol) was added over 10 minutes. The reaction mixture was treated with an additional 1 mL of concentrated NH ₄ OH solution and then sealed in a pressure vessel and heating was continued for 2 hours. The reaction mixture was then cooled and treated with 100 mL of CHCl ₃ . The reaction mixture was then washed with water, 1% Na ₂ CO ₃ solution (2x) and brine. The organic portion was dried over Na ₂ SO ₄ and concentrated to give 10.6 g of tert-butyl-2- {2- [4-amino-2- (2-methoxy-20-ethyl) -1 H -imidazo [4,5- c] ] quinolin-1-yl] ethoxy} ethylcarbamate as a brown foam.

Part D

7-tert-Butyl 2- {2- [4-amino-2- (2-methoxyethyl) -1 H -imidazo [4,5- c] quinolin-1-yl) ethoxy] 25 ethylcarbamate (10 6 g. 24.6 mmol) was treated with 75 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 1.5 hours, the reaction mixture was cooled and filtered to give a gummy solid. The solid was washed with EtOH and Et ₂ O and dried in vacuo to give the hydrochloride salt as a light brown solid. Dissolve the hydrochloride salt in 50 mL H ₂ O and treat with a 10% NaOH solution to form the free base.

The aqueous suspension was then concentrated to dryness and the residue was treated with CHCl ₃ . The resulting salts were removed by filtration and the filtrate was concentrated to give 3.82 g of 1- [2- (2-aminoethoxy) ethyl] 2- (2-methoxyethyl) -1H-imidazo [4,5-c] quinolin-4-amine in the form of a tan powder.

MS 330 (M + H) ^&lt; ^{+ &gt};;

1 H NMR (300 MHz, DMSO-d 6) δ 8.10 (d, J = 8.1 Hz, 1H); 7.66 (d, J = 8.2 Hz, 1H); 7.40 (m, 1H); 7.25 (m, 1H); 6.88 (brs, 2H); 4.78 (t, J = 5.4 Hz, 2H); 3.89 (t, J = 4.8 Hz, 2H); 3.84 (t, J = 6.9 Hz, 2H); 3.54 (t, J = 5.4 Hz, 2H); 3.31 (s, 3H); 3.23 (t, J = 6.6 Hz, 2H); 2.88 (t, J = 5.3 Hz, 2H).

Example 4

N- (2- {2- [4-Amino-2- (2-methoxyethyl) -1H-imidazo (4,5-quinolin-1-yl) ethoxy} ethyl) benzamide

O

<J)

1- [2- (2-Aminoethoxy) ethyl] -2- (2-methoxyethyl) -1H-imidazo [4,5- a] quinolin-4-amine (750 mg, 2.28) mmol) was dissolved in 35 mL of anhydrous CH ₂ Cl ₂ and cooled to 0 ° C under nitrogen, Et ₃ N (0.35 mL, 2.50 mmol) and benzoyl chloride (260 µchlor, 2.28 mmol) were added to the stirred solution. The reaction mixture was then quenched by the addition of saturated NaHCO ₃ solution (30 mL) and CH ₂ Cl ₂ (30 mL) .The organic layer was separated and washed with water and brine. The product was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a tan foam.The mass spectral analysis showed the presence of the bis-amide in addition to the desired product The tan foam was treated with 1N aqueous HCl solution (50 mL) at 100 ° C for 5 hours HPLC analysis showed that all the bis-amide 10 had been converted to the desired product, and the reaction mixture was cooled to room temperature and % NaOH until pH about 11. The mixture was extracted with CHCl ₃ (3 x 30 mL). The combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a yellow solid. Purification by column chromatography (SiO ₂ , 510% MeOH / CHCl ₃ ) afforded 100 mg of N- (2- {2- [4-amino-2- (2-methoxyethyl) -1 H -imidazo [15,5] c) quinoline -1-yl] ethoxy} ethyl) benzamide as a white powder, mp 184-187 ° C.

MS 434 (M + H) ^&lt; ^{+ &gt};;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 8.40 (m, 1H); 8.06 (d, J = 8.3 Hz, 1H); 7.76 - 7.74 (m, 2H); 20 7.60 (d, J = 7.8 Hz, 1H); 7.54-7.37 (m, 4H); 7.19 (t, J = 7.3 Hz, 1H); 6.48 (s, 2H); 4.79 - 4.72 (m, 2H); 3.91 - 3.84 (m, 2H); 3.78 (t, J = 6.9 Hz, 2H); 3.48 (t, J = 5.5 Hz, 2H); 3.25 (s, 3H); 3.20 (t, J = 6.3 Hz, 2H);

¹³ CNMR (75 MHz, DMSO-d6) 166.7; 152.0; 151.9; 145.2; 134.8; 132.7; 131.4; 128.6; 127.4; 126.7; 121.4; 120.5; 115.1; 70.4; 69.4; 69.2; 58.4; 45.5; 27.6.

Example 5 1- [2- (2-Aminoethox} ethyl) -2- (2-methoxyethyl) -6,7,8,9-tetrahydro-1 H -imidazo [4,5- c] quinolin-4-amine

1- [2- (2-Aminoethoxy) ethyl] -2- (2-methoxyethyl) -1 H -imidazo [4,5- c] quinolin-4-amine (10.0 g, 27.3 mmol) dissolved in 50 mL of trifluoroacetic acid and treated with PtO ₂ (1.0 g). The reaction mixture was shaken under H ₂ (3 kg / cm ² ). After 4 days an additional 0.5 g PtO ₂ was added and hydrogenation was continued for a further 3 hours. The reaction mixture was then filtered through celite and concentrated under reduced pressure to give a brown oil. The oil was dissolved in 200 mL H ₂ O, then basified (pH about 11) by adding 10% NaOH solution. The solution was extracted with CHCl 3 (5 x 75 mL) and the combined organic layers were dried over Na ₂ SO ₄ and concentrated to give 5.17 g of 1- (2- (24o aminoethoxy) ethyl] -2- (2-methoxyethyl) - 6,7,8,9-tetrahydro-1H-imidazo (4,5-quinolin-4-amine as a tan solid).

MS 334 (M + H) ^&lt; ^{+ &gt};;

-28GB 303462 B6 ^! 1 H NMR (300 MHz, CDCl 3) δ 5.19 (s, 2H); 4.49 (t, J = 5.4 Hz, 2H); 3.84 (t, J = 6.6 Hz, 2H); 3.71 (t, J = 5.4 Hz, 2H); 3.36 (t, J = 5.2 Hz, 2H); 3.51 (s, 3H); 3.15 (t, J = 6.6 Hz, 2H); 2.95 (m, 2H); 2.82 (m, 2H); 2.76 (t, J = 5.1 Hz, 2H); 1.84 (m, 4H); 1.47 (br s, 2H).

Example 6 N- (2- {2- [4-Amino-2- (2-methoxyethyl) -6,7,8,9-tetrahydro-17 H -imidazo [4,5- c] quinolin-1-yl] ethoxy (ethyl) benzamide

1- [2- (2-Aminoethoxy) ethyl] -2- (2-methoxyethyl) -6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinolin-4-amine (1) (00 g, 3.00 mmol) was dissolved in 30 mL of anhydrous CH ₂ Cl ₂ and cooled to 0 ° C under nitrogen. Et ₃ N (0.84 mL, 6.00 mmol) and benzoyl chloride (348 μΙ, 3.00 mmol) were added to the stirred solution and the reaction was allowed to warm to room temperature overnight. The reaction mixture was then quenched by the addition of saturated NaHCO ₃ solution (30 mL). The organic layer was separated and the fluff and buffers were dried over Na 2 SO 4 and corrected under reduced pressure to give a yellow oil. The oil was dissolved in a minimum amount of hot MeOH and then treated with Et ₂ O (50 mL), causing a white precipitate to form. The solid was isolated by filtration and dried under vacuum to give 476 mg of <RTI ID = 0.0> N- (2- {2- [4-amino-2- (2-methoxyethyl) -6,7,8,9-tetrahydro-17H-imidazo </RTI> [ 4,5-c] quinolin-1-yl] ethoxy} ethyl) benzalide as a white powder, mp 141-143 ° C;

MS438 (M + H +;

¹ H NMR (300 MH, DMSO-d ₆ ) δ 8.36 (t, J = 5.4 Hz, 1H); 7.78-7.76 (m, 2H); 7.54 - 7.42 (m, 3H); 5.68 (s, 2H); 4.43 (t, J = 5.4 Hz, 2H); 3.75 - 3.69 (m, 4H); 3.48 (t, J = 6.0 Hz, 2H); 3.37 (t, J = 5.5 Hz, 2H); 3.24 (s, 3H); 3.07 (t, J = 6.9 Hz, 2H); 2.91 (m, 2H); 2.63 (m, 2H); 1.70 (m, 4H);

¹³ C NMR (75 MHz, DMSO-d ₆ ) 166.7; 151.3; 149.3; 146.2; 138.5; 134.8; 131.4; 128.6; 127.5; 124.9; 105.6; 70.5; 69.3; 58.4; 44.6; 32.7; 27.6; 23.8; 23.0; 23.0.

Analysis: Calculated for C ₂₄ H ₃₁ N ₅ O ₃ :% C, 65.88; % H, 7.14; % N, 16.01; found:% C, 65.55; % H, 7.15; % N, 15.87.

-29EN 303462 B6

Example 7

2- (2-Methoxyethyl) -1- {2- [2- (methylamino) ethoxy] ethyl} -1 H -imidazo [4,5- c] quinolin-4-amine

Part A

A round bottom flask was charged with sodium hydride (60% oil dispersion, 9.1 g, 228 mmol) and washed with hexanes (3x) under nitrogen. The dried sodium hydride was treated with 800 ml of anhydrous THF. A solution of tert-butyl 2- (2-azidoethoxy) ethylcarbamate (41.9 g, 182 mmol) in 200 mL of THF was then added over 40 minutes to a stirred solution of sodium hydride. After the addition was complete, the reaction was stirred for an additional 20 minutes, followed by the addition of methyl iodide (13.6 mL, 218 mmol). After stirring overnight, the reaction was quenched with 300 mL of saturated NaHCO 3 solution. The reaction mixture was then treated with 200 mL H ₂ O and 1 L Et ₂ O. The organic phase was separated and washed with water and brine. The organic portion was then dried over MgSO ₄ and concentrated under reduced pressure to give 41.9 g of tert-butyl 2- (2-azidoethoxy) ethyl (methyl) carbamate as a yellow liquid.

Part B

A solution of tert -butyl 2- (2-azidoethoxy) ethyl (methyl) carbamate (41.9 g, 170 mmol) in 600 mL of MeOH was treated with 2.5 g of 10% Pd on carbon and shaken under H ₂ (3 kg / cm ² ) for 24 hours. The solution was then filtered through a total pad and concentrated to give 37.2 g of crude tert-butyl 2- (2-aminoethoxy) ethyl (methyl) carbamate as a light yellow liquid.

Part C

A stirred solution of 4-chloro-3-nitrochinoIinu (32.3 g, 155 mmol) in 400 mL of anhydrous CH ₂ C1 ₂ under N ₂ was treated with triethylamine (43.1 mL, 310 mmol) and adverts -butyl- 2- (2-aminoethoxy) ethyl 30 (methyl) carbamate (37.2 g, 171 mmol). After stirring overnight, the reaction mixture was washed with water (2 x 300 mL) and brine (300 mL). The organic portion was dried over Na ₂ SO ₄ and concentrated to give a brown oil. Column chromatography (SiO ₂ , 33% ethyl acetate / hexanes 67% ethyl acetate / hexanes) yielded 46.7 g of tert-butylmethyl- (2- {2 - [(3-nitroquinolin-4-yl) amino] ethoxy) ethyl) carbamate as a yellow solid.

Part D

A solution of N-tert-butylmethyl- (2- {2 - [(3-nitroquinolin-4-yl) amino] ethoxy} ethyl) carbamate (6.56 g, 16.8 mmol) in 75 mL of toluene was treated with 0.1 mL of toluene. 5 g of 5% Pt on carbon and shaken under H ₂ (3 kg / cm ² ) for 24 hours. The solution was then filtered through a celite pad and concentrated to provide 6.8 g of crude / ^ez, sec-butyl (2- {2 - [(3 'aminoquinolin-4-yl) amino] ethoxy} ethyl (methyl) carbamate as orange syrup, which was used without further purification.

-30GB 303462 B6

Part E

A solution of tert-butyl (2- {2 - [(3-aminoquinolin-4-yl) amino] ethoxy} ethyl (methyl) carbamate? (6.05 g, 16.8 mmol) in 200 mL of anhydrous CH ₂ Cl ₂ was cooled to 0 ° C and treated with striethylamine (2.40 mL, 17.2 mmol), then methoxypropionyl chloride (1.72 mL, 17.2 mmol) was added dropwise over 5 min. The reaction mixture was then concentrated under reduced pressure to give an orange solid which was dissolved in 200 mL of EtOH and 7.2 mL of triethylamine was added and the mixture was heated to reflux and stirred under N _2. The reaction mixture was then concentrated to dryness under reduced pressure and treated with 300 mL Et ₂ O. The mixture was then filtered and the filtrate concentrated under reduced pressure to give a brown solid which was dissolved in 300 mL of CH ₂ Cl ₂ and The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to a residue. The oil was dissolved in 100 mL hot MeOH and treated with charcoal. The hot solution was filtered and concentrated to give 7.20 g of tert-butyl- {2- {2- [2- (2-methoxyethyl) -1 H -imidazo [4,5- c] quinolin-1-yl] ethoxy} ethyl (methyl) carbamate as a yellow oil.

Part F

A solution of tert-butyl (2- {2- [2- (2-methoxyethyl) -1 H -imidazo [4,5- c] quinolin-1-yl] ethoxy} ethyl (methyl) carbamate (7.20) g, 16.8 mmol) in 200 ml CH ₂ C1 ₂ was treated with MCPBA (77%, 4.32 g,

19.3 mmol). The reaction mixture, after stirring for 6 hours, was treated with a saturated NaHCO ₃ solution and the layers were separated. The organic portion was washed with water and brine, then dried with * ₂ - 4 - concentrated 7a to give 7 OS tprr-hutyl- (2- {2- [2- (2-methoxylmethyl-5-oxo-1 H -imidazo)). [4,5-c] quinolin-1-yl] ethoxy) ethyl (methyl) carbamate as a light brown solid.

Part G

A solution of tert-butyl 1- (2- {2- [2- (2-methoxyethyl) -5-oxido-1H-imidazo [4,5-c] quinolin-1-yl] ethoxy} ethyl (methyl) carbamate ( 7.05 g (15.9 mmol) in 100 mL 1,2-dichloroethane was heated to 80 ° C and treated with 5 mL concentrated NH ₄ OH solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (10 min.). (3.33 g, 17.5 mmol) The reaction mixture was treated with an additional 5 mL of concentrated NH ₄ OH solution and then sealed in a pressure vessel and heating was continued for 4 hours The reaction mixture was then cooled and treated with 100 mL of CH ₂ Cl _{2 the second} reaction mixture is then washed with water, 1% aqueous Na ₂ CO ₃ (3x) and brine. the organic portion was dried over Na ₂ SO ₄ and concentrated to afford 6.50 g / tert-butyl (2- {2- [4-amino-2- (2-methoxyethyl) -1 H -imidazo [4,5- c] quinolin-1-yl] ethoxy} ethyl (methyl) carbamate as a brown oil 40.

Part H

7-tert-Butyl (2- {2- [4-amino-2- (2-methoxyethyl) -1 H -imidazo [4,5- c] quinolin-1-yl] ethoxy} 45 ethyl (methyl) carbamate ( 6.50 g (14.7 mmol) was dissolved in 100 mL of EtOH and treated with 20 mL of 2M HCl in EtOH, and the mixture was heated to reflux with stirring.After 6 hours, the reaction mixture was cooled and filtered to give a gummy solid. The solid was washed with EtOH and Et 2 O and dried in vacuo to give the hydrochloride salt as a light brown powder.The free base was formed by dissolving the hydrochloride salt in 50 mL H ₂ O and working up

5 mL of concentrated NH ₄ OH. The aqueous suspension was extracted with CH ₂ Cl ₂ (5 x 50 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give 3.93 g of 2- (2-methoxyethyl) -1- {2- [2- (methylamino) ethoxy] ethyl} -1 H -imidazo [4,5- c] quinolin-4-amine as a tan powder.

MS 344 (M + H) ^&lt; ^{+ &gt};;

-31 GB 303462 B6

1 H NMR (300 MHz, DMSOd ₆ ) δ 8.07 (d, J = 7.7 Hz, 1H); 7.62 (dd, J = 1.0, 8.3 Hz, 1H); 7.42 (ddd, J = 1.0, 7.1, 8.2 Hz, 1H); 7.22 (ddd, J = 1.1, 7.1, 8.2 Hz, 1H); 6.49 (s, 2H); 4.75 (t, J 5.1 Hz, 2H); 3.83 (t, J = 6.8 Hz, 4H); 3.35 (t, J = 5.6 Hz, 2H); 3.30 (s, 3H); 3.21 (t, J = 6.9 Hz, 2H); 2.45 (t, J = 5.6 Hz, 2H); 2.12 (s, 3H).

Example 8 N - (2- {2- [4-Amino-2- (2-methoxyethyl) -1 H -imidazo [4,5- a] quinolin-1-yl] ethoxy} ethyl) -A ^L methylbenzamide

NH

2- (2-Methoxyethyl) -1- {2- [2- (methylamino) ethoxy] ethyl} -1 H -imidazo [4,5- c] quinolin-4-amine (1.00 g, 2.92 mmol) was dissolved in 30 mL of anhydrous CH ₂ Cl ₂ and cooled to 0 ° C under N ₂ . Et ₃ N (0.81 mL, 5.81 mmol) and benzoyl chloride (340 μΙ, 2.92 mmol) were added to the stirred solution and the reaction was allowed to warm to room temperature overnight. The reaction mixture was then quenched by the addition of saturated NaHCO ₃ solution (30 mL) and CH ₂ Cl ₂ (30 mL). The organic layer was separated and washed with water and brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. Purification by column chromatography (SiO ₂ , 3% MeOH / CHCl 3 saturated with aqueous NH ₄ OH) gave the product as a colorless foam. Crystallization from PrOAc and hexanes gave 540 mg of N - [2- {2- [4 amino-2- (2-methoxyethyl) -1 H -imidazo [4,5- c] quinolin-1-yl] ethoxy} ethyl) - N-methylbenzamide as a white powder, mp 93.5-97.0 ° C;

MS: 448 (M + H);

Ή NMR (500 MHz, DMSO-d ₆ , 60 ° C) δ 8.04 (d, J = 7.7 Hz, 1H); 7.63 (dd, J = 0.9, 8.2 Hz, 1H); 7.42-7.33 (m, 4H); 7.23-7.19 (m, 3H); 6.24 (s, 2H); 4.74 (m, 2H); 3.86 (m, 2H); 3.82 (t, J = 6.8 Hz, 2H); 3.51 (m, 2H); 3.40 (m, 2H); 3.29 (s, 3H); 3.18 (t, J = 6.7 Hz, 2H); 2.75 (br s, 3H);

Analysis; calcd for C ₂₅ H ₂ 9 N ₅ O _3:% C, 67.09; % H, 6.53; % N, 15.65; found:% C, 67.08; % H, 6.56; % N, 15.58.

Example 9

2- (2-Methoxyethyl) -1- {2- [2- (methylilamino) ethoxy] ethyl} -6,7,8,9-tetrahydro-1 H -imidazo [4,5- c] quinolin-4-amine

2- (2-Methoxyethyl) -1- {2- [2- (methylamino) ethoxy] ethyl} -1 H -imidazo [4,5- c] quinolin-4-amine (4.22 g, 12.3 mmol) was dissolved in 25 ml of trifluoroacetic acid and treated with PtO ₂ (0.5 g). The reaction mixture was shaken under H ₂ (3 kg / cm ² ). After 4 days, an additional 0.5 g of PtO ₂ was added and hydrogenation was continued for a further 3 days. The reaction mixture was then filtered through celite and concentrated under reduced pressure to give a yellow oil. This yellow oil was dissolved in 50 mL H ₂ O and extracted with 50 mL CHCl ₃ . The organic portion was removed and discarded. The aqueous portion was then basified (pH about 12) by addition of 10% NaOH solution. It was then extracted with CHCl ₃ (6 x 50 mL) and the combined organic layers were dried over Na ₂ SO ₄ and concentrated to give a brown oil. This brown oil was dissolved in 100 mL hot MeOH and treated with slg of activated carbon. The hot solution was filtered through celite and concentrated to dryness. The resulting gummy solid was combined with Et ₂ O several times to give 3.19 g of 2- (2-methoxyethyl) -1- {2- [2- (methylamino) ethoxy] ethyl} -6,7 _J 8,9- tetrahydro-1H-imidazo [4,5-c] quinolin-4amine as an off-white powder.

MS 348 (t + H);

1 H NMR (300 MHz, CDCl 3) δ 4.84 (s, 2H); 4.48 (t, J = 5.7 Hz, 2H); 3.84 (t, J = 6.7 Hz, 2H); 3.70 (t, J = 5.7 Hz, 2H); 3.46 (t, J = 5.1 Hz, 2H); 3.36 (s, 3H); 3.14 (t, J = 6.7 Hz, 2H); 2.96 (m, 2H); 2.83 (m, 2H); 2.65 (t, J = 5.1 Hz, 2H); 2.36 (s, 3H); 1.85 (m, 4H).

Example 10

N- (2- {2- [4-Amino-2- (2-methoxyethyl) -6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinolin-1-yl] ethoxy (ethyl) - N -methylbenzamide

2- {2-Methoxyethyl) -1- {2- [2- (methylamino) ethoxy] ethyl} -6,7,8,9-tetrahydro-1 H -imidazo [4,5- c] quinoline-4- The amine (750 mg, 2.16 mmol) was dissolved in 20 mL of anhydrous CH ₂ Cl ₂ and cooled to 0 ° C under N ₂ . Et ₃ N (0.60 mL, 4.32 mmol) and benzoyl chloride (250 μΐ, 2.16 mmol) were added to the stirred solution and the reaction was allowed to warm to room temperature over the reaction. NaHCO ₃ solution (30 mL) and CH ₂ Cl ₂ (30 mL)

303462 B6 was separated and washed with water (3x) and brine, dried over Na ₂ SO 4 and concentrated under reduced pressure. Purification by column chromatography (SiO ₂ , 3% MeOH / CHCl ₃ saturated with aqueous NH ₄ OH) gave the product as a colorless foam. The foam was concentrated from isopropyl alcohol to give a syrup which solidified upon standing. The solid was dried in vacuo to give 408 mg of N - (2- {2- [4-amino-2- (2-methoxyethyl) -6,7,8,9-tetrahydro-1 H -imidazo [4], <RTIgt; 5-c] quinolin-1-yl-ethoxyethyl-N, N-methylbenzamide as an off-white powder. Mp 83.0-87.0 ° C;

MS: 452 (M + H) ^&lt; ^{+ &gt};;

1 H NMR (500 MHz, DMSO-d ₆ , 60 ° C) δ 7.37 (m, 3 H); 7.23 (m, 2H); 5.46 (s, 2H); 4.43 (m, 2H); 3.76 (t, J = 6.8 Hz, 2H); 3.68 (m, 2H); 3.50 (m, 2H); 3.42 (m, 2H); 3.27 (s, 3H); 3.05 (t, J = 6.4 Hz, 2H); 2.92 (m, 2H); 2.80 (s, 3H); 2.65 (m, 2H); 1.74 (m, 4H);

Calcd for C ₂₅ H ₃₃ N ₅ O ₃ * 0.30 C ₃ H ₈ O:% C, 66.24; % H, 7.60; % N, 14.91; found:% C, 65.86; % H, 7.81; % N, 15.10.

Example 11

1- {1 - [(2-Piperidin-4-ylethoxy) methyl] propyl} -1 H -imidazo [4,5- c] quinolin-4-amine NH ₂

Part A

Using the general procedure of Part A of Example 1, 4-piperidinethanol (10 g, 77.4 mmol) was reacted with di- tert -butyl dicarbonate (17.7 g, 81.3 mmol) to give 13.1 g / tert-butyldicarbonate. butyl 4- (2-hydroxyethyl) piperidine-1-carboxylate as a transparent oil.

PartB

To a solution of imidazole (3.89 g, 57.1 mmol) and triphenylphosphine (14.98 g, 57.1 mmol) in dichloromethane (350 mL) was added iodine (7.97 g) in three portions. After five minutes, a solution of the material from Part A in dichloromethane (70 mL) was added. The reaction mixture was stirred at room temperature overnight. More iodine (7.97 g) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium thiosulfate (2x), brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure to give an oily residue. The residue was purified by column chromatography (silica gel eluted with 20% ethyl acetate in hexanes) to give 15.52 g of p-butyl 4- (2-iodoethyl) piperidine-1-carboxylate as a pale yellow oil.

- 34GB 303462 B6

Part C

Under a nitrogen atmosphere, 2- (1 H -imidazo [4,5- c] quinolin-1-yl) butan-1-ol (6.5 g,

26.9 mmol) was added in three portions to a suspension of sodium hydride (1.4 g, 60%, 35.0 mmol) in anhydrous V, N-methyl formide. The reaction mixture was allowed to stir for 45 minutes after which time gas evolution ceased. Tert-Butyl 4- (2-iodoethyl) piperidine-1-carboxylate (10.05 g, 29.6 mmol) was added dropwise over 15 minutes. The reaction mixture was allowed to stir at room temperature for 2.5 hours, then heated to 100 ° C and stirred overnight. Analysis by HPLC showed that the reaction was about 35% complete. Saturated ammonium chloride solution was added, the resulting mixture was allowed to stir for 20 minutes and then extracted with ethyl acetate (2x). The ethyl acetate extracts were washed with water (2x) and then brine, combined, dried over sodium sulfate, filtered, and then concentrated under reduced pressure to give a brown oil. The oil was purified by column chromatography (silica gel eluted sequentially with 30% ethyl acetate in hexanes, 50% ethyl acetate in hexanes and ethyl acetate) to give 2.2 g of tert -butyl 1-4- {2- (2- (1-diimidazo [4]). (5-c] quinolin-1-yl) butoxy] ethyl) piperidine-1-carboxylate.

Part D

Using the general method of Example 1 of Part H, the material of Part C was oxidized to give tert-butyl-4- {2- [2- (5-oxido-1 H -imidazo [4,5- c] quinolin-1]). (yl) butoxy] ethyl) piperidine-1-carboxylate as an oil.

PartE

To a solution of the material from Part D in dichloromethane (20 mL) was added ammonium hydroxide solution (20 mL). A solution of tosyl chloride (0.99 g, 5.2 mmol) in dichloromethane (10 mL) was then added over 5 minutes. The resulting biphasic reaction mixture was allowed to stir overnight. The reaction mixture was diluted with chloroform and saturated sodium bicarbonate solution, filtered, and concentrated under reduced pressure to give a brown amorphous material. This material was purified by column chromatography (silica gel eluted first with 50% ethyl acetate in hexanes and then ethyl acetate) to give 1.0 g of tert-butyl-4- {2- [2- (4-amino-1H-imidazo [4]). (5-c] quinolin-1-yl) butoxy] ethyl) piperidine-1-carboxylate as a pale yellow glassy foam.

Part F

/Erc-butyM-{2-[2-(4~amino-l//-imidazo[4.5-e]quinolin-l~yl)butoxy]ethyl)piperidine-1-carboxylate (1.00) were mixed under a nitrogen atmosphere. g, 2.1 mmol) and 2N ethanolic hydrochloric acid (10 mL, 20 mmol) and the solution was stirred at room temperature for 14 h.

The solvent was removed in vacuo and the resulting solid was dissolved in water. Saturated aqueous sodium carbonate was added until pH 10. After extraction with dichloromethane (3x), the organic fractions were combined, washed with brine, dried (Na ₃ SO ₄ ), filtered and most of the solvent was removed in vacuo. Hexane was added to precipitate. Vacuum filtration gave 0.5 g of 1- {1 [(2-piperidin-4-ylethoxy) methyl] propyl} -1 H -imidazo [4,5- c] quinolin-4-amine as a tan powder.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.34 (bs, 1H), 8.19 (d, J = 8.49 Hz, 1H), 7.61 (dd, J = 8) 31, 1.13 Hz, 1H), 7.45-7.39 (m, 1H); 7.25-7.19 (m, 1H), 6.55 (s, 2H), 5.25-5.15 (m, 1H), 4.00-3.80 (m, 2H) ), 3.5-3.3 (m, 2H), 2.8-2.64 (m, 2H), 2.22-2.11 (m, 2H), 2.09-1, 99 (m, 2H), 1.8-1.63 (bs, 1H), 1.37-1.0 (m, 5H), 0.95-0.7 (m, 5H);

¹³ C-NMR (75 MHz, DMSO-d ₆ ): δ 152.8; 145.8; 140.6; 133.0; 127.8; 127.0; 126.9; 121.3; 121.0; 115.5; 71.8; 68.1, 58.4; 46.1; 36.3; 33.1; 32.7; 24.5; 9.9;

MS (CI) m / e 368.259 (368.2450 calcd for C 8 H 11 N 2 O).

-35GB 303462 B6

Example 12

5- [2- (4-Amino-1H-imidazo [4,5-c] quinolin-1-yl) ethoxy] -N-methyl-N-phenylpentanamide

Using the general procedure of Part C and D of Example 11, 2- (1 H -imidazo (4,5-c) quinolin-1-yl) ethanol (0.63 g, 2.9 mmol) and 5-bromo-2-ol were combined. N-methyl-N-phenylpentanamide (1.3 g, 4.8 mmol) to give 0.24 g of 5- [2- (5-oxido-1H-imidazo [4,5-c] quinolin-1-one); yl) ethoxy] -, N-methyl-N-phenyl-tanamide as a colorless oil. The resulting V-oxide product was also dissolved in dichloromethane and trichloroacetyl isocyanate (0.11 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and then the solvent was removed in vacuo. The resulting oil was dissolved in methanol and sodium methoxide (0.2 mL, 25 wt% in methanol) was added slowly. The reaction was maintained overnight and then concentrated in vacuo. Purification by column chromatography (silica gel, 9: 1 ethyl acetate / methanol) afforded 24 mg of 5- [2- (4-amino-1 H -imidazo [4,5- c] quinolin-1-yl) ethoxy] -4 H -methyl N -phenyls adhered to tanamide as a white solid.

1 H NMR (300 MHz, CDCl ₃ ) δ 7.94 (d, J = 8.1 Hz, 1H), 7.83 (m, 2H), 7.52 (dt, J = 7.7; 1.3 Hz, 1 H), 7.41-7.28 (m, 4 H), 7.12 (d, J = 7.8 Hz, 2 H), 5.55 (br s, 2 H) 4.65 (t, J = 5.3 Hz, 2H), 3.85 (t, J = 5.3 Hz, 2H), 3.31 (t, J = 6.3 Hz, 2H) 1.24 (s, 3H), 2.02 (m, 2H), 1.56 (m, 2H);

1.40 (m, 2H);

IR (KBr) 3429.3104, 2946, 2877, 1646, 1595, 1584, 1532, 1496, 1482, 1398, 1360, 1254, 1121, 749, 705 cm ^-1 ;

MS (EI) m / e 417.2160 (417.2165 calcd for C 24 H 27 N 5 O 2).

Example 13

5- [2- (4-Amino-1H-imidazo [4,5-c] quinolin-1-yl) ethoxy] -N-butyl-N-phenylpentanamide

2- (1H-imidazo [4,5-c] quinolin-1-yl) ethanol and 5-bromo-N-butyl-N-phenylpentanamide were mixed and worked up according to the general procedure described in Example 12. Purification by column chromatography ( silica gel, 98: 2 ethyl acetate / methanol) afforded 5- [2- (4-amino-1 H -imidazo [4,5- c] quinolin-1-yl) ethoxy] ethoxy] -N-butyl-N-phenylpentanamide in the form of a colorless oil.

-36EN 303462 B6 ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93 (d, J = 8.0 Hz, 1H), 7.87-7.85 (m, 2H), 7.54 ( dt, J = 7.7;

1.1 Hz, 1 H), 7.41-7.29 (m, 4 H), 7.10 (d, J = 7.2 Hz, 2 H), 6.20 (br s, 2 H), 4 66 (t, J = 5.2 Hz, 2H), 3.85 (t, J = 5.2 Hz, 2H), 3.66 (t, J = 7.5 Hz, 2H), 3.31 (t, J = 6.2 Hz, 2H), 1.96 (t, J =

7.2 Hz, 2 H), 1.56-1.25 (m, 8 H); 0.88 (t, J = 7.2 Hz, 3H);

MS (EI) m / e 459.2631 (459.2634 calcd for C ₂₇ H ₃₃ N ₅ O ₂ ).

Example 14 io

Methyl [2- (4-amino-1H-imidazo [4,5-e] quinolin-1-yl) butoxy] acetate

2- (4-Amino-1H-imidazo [4,5-c] quinolin-1-yl) butan-1-ol (25 mg, 0.0975 mmol) was placed in a 2 dram vial (7, 4 ml). Sodium hydride (5 mg, 60% dispersion in mineral oil 0 117 mmol) and N N -dimethylformamide (1 mL) were added. * Ampoule ³ nmíetiií »no nitrqTvukOvv vibrator for 15 minutes at room temperature to allow formation of the alkoxide. Methyl bromoacetate (11 μΐ, 0.117 mmol) was added. The reaction mixture was subjected to ultrasonic vibrations at room temperature for 1.5 hours. The reaction mixture was analyzed by LC / MS to confirm formation of the desired product. The reaction mixture was purified by semi-preparative HPLC using

Methods A.

Mass measurement (Da): theoretical mass = 328.1535, measured mass = 328.1534.

Examples 15 to 34

The compounds in the table below were prepared according to the synthetic method of step (7) of Reaction Scheme II above, using the following general method.

To a tube containing a solution of 1- [2- (2-aminoethoxy) ethyl] -2-butyl-1H-imidazo [4,5-c] quinolin-4-amine (25 mg, 77 gmol) in dichloromethane (5 mL) acid chloride (84 gmol) was added.

The tube was sealed and then placed on a shaker at room temperature for 20 hours. The solvent was removed by centrifugation in vacuo. The residue was purified by semi-preparative HPLC using Method B described above. The table below shows the free base structure and the measured exact weight (Μ + H).

-37GB 303462 B6

Example number Free base structure Exact weight (measured) 15 Dec T f ». ° Ά 396.2404 16 ° Ύ to 412.2717 ° N 04, 17 OV Λ · iOV ⁷ “^ Ó \ ΛΌ 424.2717 18 _Οχ 432.2407 1 ¹ 1 i

- 38 GB 303462 B6

Example number Free base structure Exact weight (measured) 19 Dec at 7 ^ -N / - r \ 438.2748 + O NH, ώ 20 May M s ^Ο Ά 446.2560 i 1 Π 21 at CH, 450.2318 Hz 22nd X? at \ X \ 452.2116 1

-39GB 303462 B6

Example number Free base structure Exact weight (measured) M4, CH, II -N! - ^Z _ / AA 23 at with 457.2369 X p <K. NH, ΐι Ί AA 24 at with 457.2333 0- ^ y X5 χχνΧ 25 at 460.2693 \ y / = \ in) 1 1 NH, fy N y- ‘ N 26 (y with 462.2529 ° Λ y '^ ^CH ' N > - O 1 0

-40EN 303462 B6

Example number Free base structure Exact weight j (measured) 27 Mar: WH, ru i _.X u s ° Ά_ 462.2502 o ^ o-o ' 28 X. o V 467.1952 1 29 CH ix ^ 'c \ ₀ 472.2708 30 Γ * X 476.2659

-41 GB 303462 B6

Example number Free base structure Exact weight (measured) 31 Μ σ \ 482.2568 1 32 500.2246 33 w, F 500.2252 and and 1 34 1 l V * />> řč <AO ^ _f F 500.2217 1

-42EN 303462 B6

Examples 35 to 51

The compounds in the table below were prepared according to the synthetic method of step (7) of Reaction Scheme 11 above, using the following general method.

To a tube containing a solution of 1- {1 - [(2-piperidin-4-ylethoxy) methyl] propyl} -1 H -imidazo [4,5- c] quinolin-4-amine (25 mg) in dichloromethane (5 mL) acid chloride (1.1 eq) was added.

The tube was sealed and then placed on a shaker at room temperature for 20 hours. The solvent was removed by centrifugation in vacuo. The residue was purified by semi-preparative HPLC using Method B described above. The table below shows the free base structure and the measured exact weight (Μ + H).

Example number Free base structure Exact weight (measured) 35 NH, JCQ · V-in / · 436.2683 36 NH, 452.3014

-43 GB 303462 B6

Example number Free base structure Exact weight (measured) 37 nh, 'O ³ -0 464,3045 38 ! &> Čr ^ \ O—- 472.2717 39 tp A> θ / ν Q 0 486.2878 40 and 1 NH, JQ3 cry Q F 490.2592 j

-44 GB 303462 B6

Example number Free base structure Exact weight (measured) 41 Χχ ·> Rx 492.2419 42 j3 Rx '0 497.2682 43 X,  Χ? Γ 0 500.3022 44 Γ Αλ ďx CH. \ ^ q ° -CH, 502.2824

-45GB 303462 B6

Example number Free base structure Exact weight (measured) 45 NH, Crx c, O 507.2281 46 ŮÝ 473.2686 47 r 512,3038 48 NH, _kI A_zN H) rr '' - ·., / Ch, <κ ~~ \ \ o 516.2965

-46EN 303462 B6

Example number Free base structure Exact weight 1 (measured) 49 NH, Λ u n O 522.2836 50 TO 540.2534 51 NH _and νΧΛ XX? in MA X 0 556.2521

-47EN 303462 B6

Examples 52 to 66

The compounds in the table below were prepared according to the synthetic method of step (7) of Reaction Scheme 11 above, using the following general method.

1- [2- (2-Aminoethoxy) ethyl] -1 H -imidazo [4,5- c] quinolin-4-amine (20 mg) and 1-methyl-2-pyrrolidinone (5 mL) were mixed in a test tube. and subjected to ultrasonic vibrations from heating to obtain a solution. Acid chloride (1.1 eq) was added. The tube was sealed and then placed on a shaker at room temperature for 20 hours. Centrifugation in vacuo removed the solvent. The residue was purified by semi-preparative HPLC using Method B described above. The table below shows the free base structure and the measured exact weight (Μ + H).

Example number Free base structure Exact weight (measured) 52 356.2093 53 NH, 376.1783 1

-48 GB 303462 B6

Example number Free base structure Exact weight (measured) 54 NH, 382.2260 55 X, X 390.1949 56 Nh, Č> s 396.1503 57 05 / u \ X- ,. 401.1707

-49GB 303462 B6

Example number Free base structure Exact weight (measured) 58 aX> u p ° x 404.2105 59 TO. 406.1855 60 JCC '> O\ o ^ CXo '' · 406.1861 61 NH, u s ° ~ Λ '' N ^ -N 411.1320 J

- 50GB 303462 B6

Example number Free base structure Exact weight (measured) 62 eX in 420.2047 63 NH, mus ^OA ^ co 426.1912 64 NH, ~ W 444.1628 65 NH, JŮ3 U S F 444.1655 ..

-51 CZ 303462 B6

Induction of cytokines in human cells

An in vitro human blood cell system is used to evaluate cytokine induction. The effect is based on the measurement of interferons and tumor necrosis factor (a) (IFN and TNF, respectively) secreted into the culture medium as described by Testerman et al. in "Cytokine Induction by the Immunomodulators Imiquimod and S-27609", Journal of Leukocyte Biology, 58, 365-372 (September, 1995).

Blood cell preparation for culture

Whole blood from healthy human donors is collected by venipuncture into EDTA vacuum tubes. Peripheral blood mononuclear cells (PBMC) are separated from whole blood by density gradient centrifugation using Histopaqué-1077. The PBMCs are washed twice with Hanoi balanced equilibrated saline and then suspended at 3-4 x 10 ⁶ cells / ml in RPMI pool.

The PBMC suspension is added to 48-well sterile flat-mouth tissue culture plates (Costar, Cambridge, Massachusetts or Becton Dickinson Labware, Lincoln Park, New Jersey) containing an equal volume of RPMI file media containing the test compound.

Preparation of compound

Compounds are dissolved in dimethylsulfoxide (DMSO). The concentration of DMSO to be added to the culture wells should not exceed a final 1% concentration.

Incubation

The test compound solution is added to the first well containing the RPMI pool and the wells are serially diluted. The PBMC suspension is then added to the wells in the same volume to bring the concentration of the test compound to the desired range. The final concentration of PBMC suspension is 1.5 - 2 x 10 ⁶ cells / ml. Plates are coated with sterile plastic covers, mixed gently and then incubated for 18-24 hours at 37 ° C in an atmosphere of 5% carbon dioxide. Separation

After incubation, the plates are centrifuged for 5-10 minutes at 1000 rpm (about 200 x g) at 4 ° C. The culture-free supernatant is removed with a sterile polypropylene pipette and transferred to sterile polypropylene tubes. The samples are maintained at -30 to -70 ° C until analysis. Samples are analyzed for interferon (a) and tumor necrosis factor (a) by ELIS A test.

Tumor necrosis factor (a) interferon (a) analysis by ELISA

Interferon (a) concentrations were determined by an ELISA assay using the Human Multi-Species Kit from PBL Biomedical Laboratories, New Brunswick, NJ. Results are shown in pg / ml.

io Tumor necrosis factor (a) concentrations are determined using an ELISA kit available from Genzyme, Cambridge, MA; R&D Systems, Minneapolis, MN; or Phamningen, San Diego, CA. Results are shown in pg / ml.

The table below shows the lowest concentration found by interferon induction and the lowest concentration found by tumor necrosis factor induction for each compound. The symbol indicates that no induction was seen at any of the concentrations tested; generally the highest concentration tested was 10 or 30 μΜ.

-53 CZ 303462 B6

Induction of cytokines in human cells Lowest effective concentration (μΜ) Example number Interferon • Tumor Rectrosis Factor 12 3.33 4 13 10 4 14 0.37 4 15 Dec 0.1 1 16 0.1 1 17 1 1 18 1 10 19 Dec 1 10 20 May 0.1 10 21 1 10 22nd 0.1 10 23 1 10 24 1 10 25 1 10 26 1 10 27 Mar: 1 10 28 1 10 29 1 10 30 1 10 31 4 10 32 * 10 33 * 10 34 + 10 35 and 0.1 1 36 1 1 37 1 1 38 1 L 10

-54EN 303462 B6

Induction of cytokines in human cells Lowest effective concentration (μΜ) Example number Ijiterferon Tumor necrosis factor 39 i! and 10 40 1 1 41 o _s i 1 42 1 1 43 1 10 44 1 1 45 OJ 1 46 0.1 1 47 1 ♦ 48 0.1 10 49 1 10 50 ¹ 1 51 10 10 52 10 10 53 10 10 54 10 10 55 1 10 56 1 10 57 10 * 58 10 10 59 10 10 60 10 10 61 10 10 62 1 10 63 + 10 64 10 + 65 * i * 66 * 1 ... ! *

Claims (9)

PATENT CLAIMS 1. A limidazo [4,5-c] ehinoline derivative of the formula 1 or a 6,7,8,9-tetrahydroimidazo [4,5-c] quinoline derivative of the formula II X is -CHR ₅ -alkyl- -CHRs- or -CHR _s -alkenyl; io R 1 is selected from the group consisting of a residue -R ₄ -CR; -ZR ₆ -alkyl; -R ₄ -CR-ZR ₆ -alkenyl; ₄ -R 15 -C-R ^ -aryl ZR I; -R ₄ -CR ₃ -Z-R 6 -heteroaryl; R 1 -CR 1 -Z-R 1 -heterocyclyl; -CR ₄ R, -ZH; —R.jN R - — R R — R R — alkyl 1; 20-Kt-NR 3 -CR 1 -R 6 -alkenyl; —R ₄ —NR? ^- CR ₃ - Rfj ^- aryl 1; -R ₄ -NR ₇ -C R 1 -R ₆ -heteroaryl; -R 1 -R N -CR 5 -R 6 -heterocyclyl; and -R ₄ -NR ₇ -CR ₃ -R ₈ ; each Z independently represents -NR _S - -O- or -S-; -56EN 303462 B6 R ₂ is selected from the group consisting of residues - a hydrogen atom; - alkyl; 5-alkenyl; -aryl; -heteroaryl; - heterocyclyl; -alkyl-Y-alkyl; io-alkyl-γ-alkenyl; alkyl-Y-aryl; and alkyl or alkenyl substituted with one or more substituents selected from the group consisting of residues 15 -OH; - halogen; -N (R ₅ ) ₂ ; - CO-N _{(R) 2;} - CO-C 1-10 alkyl; 20 - _CO-O-Ci-I0 alkyl; -N ₃ ; -aryl; - heteroaryl; - heterocyclyl; 25-CO-aryl; and CO-heteroaryl; each R ₃ is = O or = S; Each R 4 is independently alkyl or alkenyl, which may be interrupted by one or more -O-; each R ₅ is independently H or C | _i _O alkyl; R 6 represents a bond, alkyl or alkenyl, which may be interrupted by one or more -O- groups; R ₇ is H, C 1-10 alkyl or arylalkyl; or R ₄ and R ₇ together form a saturated heterocyclic ring; R ₈ represents H or C _1-10 alkyl; or R ₇ and R ₈ together form a heterocyclic ring; each Y is independently -O- or -S (O) ₀ _ ₂ -; 45 n is 0 and 4; and -57CZ 303462 B6 each R present is independently selected from the group consisting of C | _O _i alkyl, Ciioalkoxyskupiny, hydroxy, halogen and trifluoromethyl; Or a pharmaceutically acceptable salt thereof; wherein the alkyl group contains 1 to 10 carbon atoms; an alkenyl group containing 2 to 10 carbon atoms; aryl is selected from the group consisting of phenyl, naphthyl, biphenyl, fluorenyl and indenyl; 15 heteroaryl is selected from the group consisting of furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothienyl, carbazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazole benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl; 20 heterocyclyl is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl; and the aryl, heteroaryl and heterocyclyl group may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, 25 cyano, methoxy, trifluoromethyl and trifluoromethoxy. A compound according to claim 1, wherein X is -CH 2 -CH 2 -, or a salt thereof. 30 An imidazo [4,5-c] quinoline derivative of the Formula I or a 6,7,8,9-tetrahydroimidazo [4,5-c] quinoline derivative of the Formula II according to claim 1, wherein R ₇ is H, alkyl or - alkyl-O-alkyl, or salts thereof. An imidazo [4,5-c] quinoline derivative of the Formula I or a 6,7,8,9-tetrahydroimidazo 35 [4,5-quinoline derivative of the Formula II according to claim 1, wherein R 1 is -R 4-NR 7 -CR 3 R 6 - alkyl or -R 4 -NRr-CR ₃ -R ₆ -aryl, R ₃ is = O, R 6 is a bond, and R ₇ is H, or salts thereof. The limidazo [4,5- b] quinoline derivative of the Formula I or the 6,7,8,9-tetrahydroimidazo 40 [4,5-ejinoline derivative of the Formula II according to claim 1, wherein n is 0, or salts thereof. 6. A pharmaceutical composition comprising a therapeutically effective amount of the itnidazo [4,5-c] quinoline derivative of formula (I) or the 6,7,8,9-tetrahydroimidazo [4,5-c] quinoline derivative of formula (II) according to of claims 1, 2, and 3 to 5 or their respective And a pharmaceutically acceptable carrier. Use of an imidazo [4,5-quinoline derivative of the general formula 1 or a 6,7,8,9-tetrahydroimidazo [4,5-equinoline derivative of the general formula II according to claims 1, 2 and 3 to 5 or salts thereof for the preparation of a medicament for inducing cytokine biosynthesis in the treatment of atopic diseases such as atopic dermatitis, asthma, allergy, allergic rhinitis; in the treatment of systemic lupus erythematosus; When used as an adjuvant for a vaccine for cell-mediated immunity; in the treatment of chlamydia; in the treatment of viral diseases including genital warts; common warts, foot warts, hepatitis B, hepatitis C, diseases caused by herpes simplex virus type 1 and type II, moluscum contagiosum, varriola major, HIV, CMV, VZV, rhinovirus, adenovirus, influenza and parainfluenza; in the treatment of intraepithelial neoplasia, HPV-induced diseases and associated neoplasia; in the treatment of fungal diseases such as candidiasis, aspergillus infection and cryptococcal meningitis; in the treatment of cancers such as basocellular carcinoma, hairy cell leukemia, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgins lymphoma, T-cell skin lymphoma and other cancers; in the treatment of parasitic diseases such as pneumocystis camii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosomal infections and leishmaniasis; in the treatment of bacterial infections such as tuberculosis and mycobacterium avium infections; in the treatment of actinic keratosis, eczema, eosinophilia, essential thrombocythemia, leprosy, multiple sclerosis, Ommen syndrome, discoid lupus, Bowen's disease, bowenoid papulosis, alopecia areata; in the treatment of postoperative colloidal formation and other types of postoperative scars; in improving or stimulating wound healing, including chronic wounds; and in describing opportunistic infections and tumors that occur following suppression of cell-mediated immunity in transplant patients, cancer patients or HIV patients. 8. A lmidazo [4,5-quinoline derivative of the Formula V) NH N N ‘2 (V). where X is -CHR 5 -. -CHR5 -alkenyl- or -CHR5-alkenyl-; R ₂ is selected from the group consisting of residues - a hydrogen atom; - alkyl; alkenyl; -59EN 303462 B6 aryl; - heteroaryl; - heterocyclyl; alkyl-Y-alkyl; 5-alkyl-Y-alkenyl; alkyl-Y-aryl; and alkyl or alkenyl substituted with one or more substituents selected from the group consisting of residues 10 -OH; - halogen; -N (R ₅ ) ₂ ; -CO-N (R ₅ ) ₂ ; - CO-C _{[_) (alkyl;} 15 - CO-O-C 'i ₀ alkyl; -N ₃ ; -aryl; - heteroaryl; - heterocyclyl; 20-CO-aryl; and - CO-heteroaryl; each R 4 independently represents alkyl or alkenyl, which may be interrupted by one or more -O- groups; each R ₅ independently represents H or C _1-10 alkyl; R ₇ is H, alkyl or _O Ci_i arylalkyl 1; or R 4 and R ₇ together form a saturated heterocyclic ring; each Y is independently -O- or -S (O) _0-2 -; n is 0 to 4; and Each R present is independently selected from the group consisting of C _1-10 alkyl, C 1-3 _O alkoxy, hydroxy, halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof; 40 wherein the alkyl group contains 1 to 10 carbon atoms; an alkenyl group containing 2 to 10 carbon atoms; aryl is selected from the group consisting of phenyl, naphthyl, biphenyl, fluorenyl and indenyl; Heteroaryl is selected from the group consisting of furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothienyl, benzothienyl, benzothienyl, benzothienyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl; heterocyclyl is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl; and the aryl, heteroaryl and heterocyclyl groups may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, cyano, methoxy, trifluoromethyl and trifluoromethoxy. 9. A compound according to claim 8, which is a compound 15 formulas